Injection Paradigm For Administration Of Botulinum Toxins

ABSTRACT

Disorders such as headaches can be treated by administration of a botulinum toxin to a patient suffering therefrom, such as a migraine headache. A combined a fixed site/fixed dose and an optional follow the pain variable dosage and injection site paradigm is disclosed for optimizing clinical effectiveness of botulinum toxin administration for patients suffering headache, particularly chronic migraine.

CROSS REFERENCES OF RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.15/707,452, filed Sep. 18, 2017, which is a Divisional of U.S. patentapplication Ser. No. 15/057,866, filed Mar. 1, 2016, now U.S. Pat. No.9,764,011, which is a continuation of U.S. patent application Ser. No.13/863,522, filed Apr. 16, 2013, now U.S. Pat. No. 9,279,001, which is acontinuation in part of U.S. patent application Ser. No. 13/075,485,filed Mar. 30, 2011, now U.S. Pat. No. 8,501,195, which claims thebenefit of U.S. Provisional Application Ser. No. 61/319,230, filed Mar.30, 2010, and 61/320,667, filed Apr. 2, 2010, all incorporated entirelyby reference.

FIELD

Embodiments of the present invention relate to the treatment of variousdisorders, specifically to injection administration protocols utilizingbotulinum neurotoxin.

BACKGROUND

It is known that botulinum toxins can be utilized to treat a variety ofdisorders. Examples include U.S. Pat. No. 5,714,468 (migraine) issuedFeb. 3, 1998; Published U.S. Patent Application No. 20050191321(headache), Ser. No. 11/039,506, filed Jan. 18, 2005; Published U.S.Patent Application No. 20050191320 (medication overuse headache), Ser.No. 10/789,180, filed Feb. 26, 2004; and U.S. Pat. No. 7,811,587(neuropsychiatric disorders), issued Oct. 12, 2010; all incorporatedentirely by reference.

An example of a disorder treatable with botulinum toxins is chronicmigraine (CM), a disabling headache disorder, affecting 1.3% to 2.4% ofthe general population and considered the most common type of primarychronic daily headache in the United States. CM is linked withsuffering, disability, and medication overuse, and only one third of CMpatients use headache prophylactic medication. Few headache preventivetreatments have been investigated for patients with CM. Thus, thereremains a need for optimized and targeted methodologies to treat thismalady in particular, specific and useful injection and dosage paradigmsfor utilizing botulinum toxins to treating CM.

Another condition amenable to treatment with botulinum toxin isMedication Overuse Headache Disorder (MOU). It has been described as aself-sustaining, rhythmic, headache medication cycle characterized bydaily or near daily headache with irresistible and predictable use ofimmediate relief medications. Evidence supporting the existence of MOHis widely published in the medical literature.

SUMMARY OF THE INVENTION

In one embodiment, the present invention teaches a method forprophylactically treating a headache in a patient suffering from chronicmigraine headaches, the method essentially consisting of localadministration of a botulinum neurotoxin to the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles of the patient that suffers from the migraine headache, wherethe botulinum neurotoxin is administered, to the frontalis at abouttwenty units divided among four sites of injection, to the corrugator atabout ten units divided among two sites of injection; to the procerus atabout five units to one site of injection; to the occipitalis at aboutthirty units divided among six sites of injection to about forty unitsdivided among eight sites of injection; to the temporalis at about fortyunits divided among eight sites of injection up to fifty units dividedamong ten sites of injection; to the trapezius at about thirty unitsdivided among six sites of injection up to about fifty units dividedamong ten sites of injection and to the cervical paraspinal muscles atabout twenty units divided among four sites of injection, and where thebotulinum neurotoxin is injected at 31 to 39 injection sites. In oneembodiment, the botulinum neurotoxin is onabotulinumtoxin A. In anotherembodiment, the botulinum neurotoxin is a pure toxin, devoid ofcomplexing proteins. In a specific embodiment, the botulinum neurotoxinis incobotulinumtoxinA.

In another embodiment, the present invention discloses a method fortreating or reducing the occurrence of a headache in a patient withchronic migraine headaches, the method consisting essentially ofadministration of abobotulinumtoxinA to the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles of the patient that suffers from the migraine headache; whereinthe botulinum neurotoxin is administered, to the frontalis at about fromforty units to about 100 units divided among four sites of injection; tothe corrugator at about from twenty units to about fifty units dividedamong two sites of injection; to the procerus at about from ten units toabout twenty five units to one site of injection; to the occipitalis atabout from sixty units to about one hundred fifty units divided amongsix sites of injection to about from eighty units to about two hundredunits divided among eight sites of injection; to the temporalis at aboutfrom eighty units to about two hundred units divided among eight sitesof injection up to from one hundred units to about two hundred fiftyunits divided among ten sites of injection; to the trapezius at aboutfrom sixty units to about one hundred fifty units divided among sixsites of injection up to about from one hundred units to about twohundred fifty units divided among ten sites of injection and to thecervical paraspinal muscles at about from forty units to about onehundred units divided among four sites of injection; and whereinabobotulinumtoxinA is injected at 31 to 39 injection sites.

In another embodiment, the present invention discloses a method fortreating or reducing the occurrence of a headache in a patient withchronic migraine headaches, the method consisting essentially of: localadministration of a botulinum neurotoxin to the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles of the patient that suffers from the migraine headache; whereinthe botulinum neurotoxin is administered, to the frontalis at abouteighty units divided among four sites of injection; to the corrugator atabout forty units divided among two sites of injection; to the procerusat about twenty units to one site of injection; to the occipitalis atabout one hundred twenty units divided among six sites of injection toabout one hundred sixty units divided among eight sites of injection; tothe temporalis at about one hundred sixty units divided among eightsites of injection up to two hundred units divided among ten sites ofinjection; to the trapezius at about one hundred twenty units dividedamong six sites of injection up to about two hundred units divided amongten sites of injection and to the cervical paraspinal muscles at abouteighty units divided among four sites of injection; wherein thebotulinum neurotoxin is injected at 31 to 39 injection sites. In onespecific embodiment, the botulinum neurotoxin is abobotulinumtoxinA.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are presented to illustrate aspects and featuresof embodiments of the present invention.

FIG. 1 is a graph showing the results (mean change in the number ofheadaches per thirty day period) of a clinical study carried out for useof BOTOX® to inter alia treat migraine headache, showing that thepatients had fewer headaches after administration of BOTOX®. In the datashown in the Figures, the patients had been administered BOTOX® at days0, 90 and 180.

FIG. 2 is a graph showing the results (mean change in the number of dayspatients were concurrently taking acute headache pain alleviationmedication per thirty day period) of a clinical study using BOTOX® tointer alia treat migraine headache, showing that the patients had fewerdays when they were taking acute headache pain alleviation medicationafter administration of BOTOX®.

FIG. 3 is a graph showing a comparison of the percent of patients (somewho had been administered BOTOX® and some who had been administered aplacebo) who were over a thirty day period using narcotics medication tocontrol acute headache pain. FIG. 3 shows a decrease in narcotic use inthe BOTOX®-treated patients.

FIG. 4 is a graph showing a decrease in the percentage of patients whohad acute headache medication overuse in a thirty day period afteradministration of BOTOX®.

FIG. 5 is a graph showing a decrease in the percentage of patients whohad demonstrated overuse of triptans in a thirty day period afteradministration of BOTOX®.

FIG. 6 comprises two graphs showing the mean change in the number ofheadaches experienced by patients over a thirty day period afteradministration of BOTOX®, where the patients either did not have MOU(“without MOU”; left side graph) or the patients did have an MOUdisorder (right side graph). “≥15 days and ≥2 days/week” are criteriaused to determine that a patient had an MOU disorder. MOU and MOD aresynonymous terms. By definition, a patient has an MOU disorder if he orshe takes an acute medication 15 or more days per month and at leasttwice a week in the week that they are experiencing the acute pain.

FIG. 7 comprises two graphs which show the mean change from baseline inthe frequency of headaches per 30-day period in patients using (graph A)and not using (graph B) prophylactic headache medications at baseline,for a pooled population of patients. The Y-axis represents the meanchange in the number of headaches per thirty day period. “n” indicatesthe number of patients in the sample of patients evaluated.

FIG. 8 comprises two graphs which show the mean change in the number ofheadaches experienced by patients over a thirty day period afteradministration of BOTOX®, where the patients either were notconcurrently using another headache prophylaxis treatment (left sidegraph) or the patients were not concurrently using another headacheprophylaxis treatment and did have an MOU disorder (right side graph).

FIG. 9 comprises two graphs showing the mean change in the number ofheadaches experienced by patients over a thirty day period afteradministration of BOTOX®, where the patients either were notconcurrently using another headache prophylaxis treatment and did nothave an MOU disorder (left side graph) or the patients were notconcurrently using another headache prophylaxis treatment and did havean MOU disorder (right side graph).

FIG. 10 is a bar chart showing the percentage of patients over a thirtyday period after administration of BOTOX® who were also using an opioidacute headache medication.

FIG. 11 comprises two graphs which show the mean change in the number ofheadaches experienced by patients over a thirty day period afteradministration of BOTOX®, where the patients either were triptanmedication overuse patients (left side graph) or not triptan medicationoveruse patients (right side graph).

FIG. 12 comprises two graphs which shows the mean change from baseline(after administration of BOTOX®) in number of days with acute headache(analgesic) medication use by the patients, where the patients wereeither triptan medication overuse patients (left side graph) or nottriptan medication overuse patients (right side graph).

FIG. 13 comprises on the left side, a left side diagrammatic view ofhuman muscle anatomy from the shoulders up, and on the right side adiagrammatic view of the back.

FIG. 14 comprises two graphs which show the mean change from baseline inthe frequency of headaches per 30-day period for placebo non-responders(A) and responders (B).

FIG. 15 shows the mean change from baseline in the frequency ofheadaches per 30-day period, for a pooled population of patients.

FIG. 16 comprises two graphs which show mean change from baseline in thenumber of days of use of acute analgesic headache medications per 30-dayperiod for patients using (graph A) and not using (graph B) prophylacticheadache medications at baseline, for a pooled population of patients.

FIG. 17 depicts an example of fixed locations to which doses ofbotulinum toxin are administered to a patient (here in supine andsitting positions) in accordance with one embodiment of an injectionparadigm.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In certain embodiments, the dose of a botulinum toxin used according toembodiments of the present invention is less than the amount ofbotulinum toxin that would be used to paralyze a muscle, because anintent of a method according to embodiments of the present invention isnot to paralyze a muscle but to reduce a pain sensory output fromsensory neurons located in or on a muscle, or in or under the skin.

The following definitions apply herein:

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means±10% of the numerical value orrange recited or claimed.

“Alleviating” means a reduction in the occurrence of a pain, of aheadache or of a symptom of a headache. Thus, alleviating includes somereduction, significant reduction, near total reduction, and totalreduction. An alleviating effect may not appear clinically for between 1to 7 days after administration of a Clostridial toxin to a patient orsometime thereafter.

“Botulinum toxin” means a botulinum neurotoxin as either pure toxin orcomplex, native, recombinant, or modified, and includes botulinum toxintype A, type B, type C₁, type D, type E, type F, and type G. As usedherein, this term excludes non-neurotoxins, such as the cytotoxicbotulinum toxins C₂ and C₃.

“Local administration” means administration of a pharmaceutical agent toor to the vicinity of a muscle or a subdermal location in a patient by anon-systemic route. Thus, local administration excludes systemic routesof administration, such as intravenous or oral administration.

“Peripheral administration” means administration to a location away froma symptomatic location, as opposed to a local administration.

“MOU” means medication overuse headache or medication overuse headachedisorder.

“Treating” or “treatment” means to alleviate (or to eliminate) at leastone symptom (such as, for example, headache pain), either temporarily orpermanently. This can include prophylactic applications to prevent atleast one symptom of headache.

Disclosed herein are embodiments of an administration paradigm forbotulinum neurotoxins. In some embodiments, the method can includespecific injection locations and dosage amounts of botulinum toxin totreat various disorders, including, for example, CM, MOU, ND's, and thelike. In certain embodiments of the invention, the disorder can betreated by intramuscular administration of the toxin in specific amountsor ranges of amounts to specific sites within the upper torso of thepatient. In certain embodiments, such sites can include, for example,the head, the neck, one or both shoulders, in both the anterior orposterior positions. The botulinum toxin can be a botulinum toxin typeA, type B, type type D, type E, type F, or type G, or any combinationthereof. The botulinum neurotoxin can be a recombinantly made botulinumneurotoxins, such as botulinum toxins produced by E. coli. The botulinumneurotoxin can be a pure toxin, devoid of complexing proteins, such asXeomin® (incobotulinumtoxinA). In some embodiments, the amount ofincobotulinumtoxin A administered according to a method within the scopeof embodiments of the invention is similar to the amount ofonabotulinumtoxinA (such as BOTOX®) administered, as comparative studieshave suggested that one unit of IncobotulinumtoxinA has a potencyapproximately equivalent to one unit of onabotulinumtoxinA.

In addition, the botulinum neurotoxin can be a modified neurotoxin, thatis a botulinum neurotoxin which has at least one of its amino acidsdeleted, modified or replaced, as compared to a native toxin, or themodified botulinum neurotoxin can be a recombinant produced botulinumneurotoxin or a derivative or fragment thereof. In certain embodiments,the modified toxin has an altered cell targeting capability for aneuronal or non-neuronal cell of interest. This altered capability isachieved by replacing the naturally-occurring targeting domain of abotulinum toxin with a targeting domain showing a selective bindingactivity for a non-botulinum toxin receptor present in a non-botulinumtoxin target cell. Such modifications to a targeting domain result in amodified toxin that is able to selectively bind to a non-botulinum toxinreceptor (target receptor) present on a non-botulinum toxin target cell(re-targeted). A modified botulinum toxin with a targeting activity fora non-botulinum toxin target cell can bind to a receptor present on thenon-botulinum toxin target cell, translocate into the cytoplasm, andexert its proteolytic effect on the SNARE complex of the target cell. Inessence, a botulinum toxin light chain comprising an enzymatic domain isintracellularly delivered to any desired cell by selecting theappropriate targeting domain.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as, for example, albumin, or the like.In embodiments containing albumin, the albumin can be, for example,human serum albumin, or the like. The lyophilized material can bereconstituted with a suitable liquid such as, for example, saline,water, or the like to create a solution or composition containing thebotulinum toxin to be administered to the patient.

The amount of the botulinum toxin administered according to a methodwithin the scope of embodiments of the invention can vary according tothe particular characteristics of the pain being treated, including itsseverity and other various patient variables including size, weight,age, and responsiveness to therapy. To guide the practitioner,typically, no less than about 1 unit and no more than about 25 units ofa botulinum toxin type A (such as BOTOX®) is administered per injectionsite per patient treatment session. For a botulinum toxin type A such asDYSPORT® (abobotulinumtoxinA), no less than about 2 units and no morethan about 125 units of the botulinum toxin type A are administered perinjection site, per patient treatment session. In some embodiments, theamount of abobotulinumtoxinA, (such as) DYSPORT®, administered in thepresent method is about four times the amount of onabotulinumtoxinA(such as BOTOX®) administered, as comparative studies have suggestedthat one unit of onabotulinumtoxinA has a potency that is approximatelyequal to four units of abobotulinumtoxinA. For a botulinum toxin type Bsuch as MYOBLOC®, no less than about 40 units and no more than about1500 units of the botulinum toxin type B are administered per injectionsite, per patient treatment session.

Preferably, for BOTOX® no less than about 2 units and no more about 20units of a botulinum toxin type A are administered per injection siteper patient treatment session; for DYSPORT® (abobotulinumtoxinA), noless than about 4 units and no more than about 100 units areadministered per injection site per patient treatment session, and; forMYOBLOC®, no less than about 80 units and no more than about 1000 unitsare administered per injection site, per patient treatment session.

More preferably, for BOTOX® no less than about 5 units and no more about15 units of a botulinum toxin type A; for DYSPORT® (abobotulinumtoxinA),no less than about 20 units and no more than about 75 units, and; forMYOBLOC®, no less than about 200 units and no more than about 750 unitsare, respectively, administered per injection site, per patienttreatment session.

Generally, the total amount of BOTOX®, DYSPORT® or MYOBLOC®, suitablefor administration to a patient according to the methods of theinvention disclosed herein should not exceed about 300 units, about1,500 units or about 15,000 units respectively, per treatment session.

The treatment effects of the botulinum toxin can persist for betweenabout 1 month and 5 years.

Embodiments of the invention provide a targeted, fixed injectionparadigm directed to a specific set of muscles with a specific minimumnumber and volume of injections, and further provides for theadditional/optional administration of additional botulinum toxin tospecific site of selected muscles. In one embodiment, the fixed dosage(that is, a minimum dosage amount in accordance with the fixed amountsand locations specified in a package insert or prescribing information)of botulinum toxin is administered to the frontalis, corrugator,procerus, occipitalis, temporalis, trapezius and cervical paraspinalmuscles of a patient, and further a variable amount of additionalbotulinum toxin can be added to four or less of the seven head/neckareas such that the total amount of botulinum toxin administered doesnot exceed a maximum total dosage as indicated in the package insert orprescribing information accompanying a botulinum toxin-containingmedicament. The botulinum toxin can be selected from the groupconsisting of botulinum toxin types A, B, C, D, E, F and G. Botulinumtoxin type A is a preferred botulinum toxin. The botulinum toxin can beadministered in an amount of between about 1 unit and about 3,000 units,or between about 2 units and about 2000 units, or between about 5 unitsand about 1000 units, or between about 10 units and about 500 units, orbetween about 15 units and about 250 units, or between about 20 unitsand about 150 units, or between 25 units and about 100 units, or betweenabout 30 units and about 75 units, or between about 35 units and about50 units, or the like, and the alleviation of the symptoms can persistfor between about 1 month and about 5 years.

In one embodiment, a method is disclosed that utilizes a dose andinjection paradigm of 155 units of BOTOX® (typically provided as 100Units of Clostridium botulinum type A neurotoxin complex, with 0.5 mg ofhuman serum albumin, and 0.9 mg of sodium chloride in a sterile,vacuum-dried state for reconstitution), administered as 31 fixed-site,fixed-dose (5 units per) injections, and an optional 40 units in up to 8additional injection sites using a follow-the-pain regimen per treatmentcycle (for up to 39 injection sites and up to 195 units total). Thetotal dose is divided across 7 head/neck muscles and is repeated every12 weeks.

In an embodiment, a method for treating a migraine such as, for example,CM, can encompass administration of a botulinum toxin to 31 fixedinjection sites across seven head/neck muscles. Optionally, up to 8additional injection sites into three specific muscles, where thesethree muscles are subset of the above seven head/neck muscles, areadministered utilizing a follow-the pain regimen to provide flexibilityin the dose/muscle for the three muscles, to address individual patientneeds. In particular embodiments, a minimum of 155 units of a botulinumtoxin type A up to about 195 units of a botulinum toxin type A, areadministered in accordance with a particular injection paradigm hereindisclosed.

In a specific embodiment, a method for treating CM comprises the step oflocal administration of a botulinum neurotoxin to the frontalis,corrugator, procerus, occipitalis, temporalis, trapezius and cervicalparaspinal muscles of the CM patient such that the botulinum neurotoxinis administered to the frontalis at about twenty units divided amongfour sites of injection, to the corrugator at about ten units dividedamong two sites of injection, to the procerus at about five units to onesite of injection, to the occipitalis at about thirty units dividedamong six sites of injection to about forty units divided among eightsites of injection; to the temporalis at about forty units divided amongeight sites of injection up to fifty units divided among ten sites ofinjection, to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, such that the total amount ofbotulinum neurotoxin administered is from about 155 units to about 195units injected at from 31 to 39 injection sites, respectively.

In one aspect, embodiments of the present invention are based on thediscovery that a botulinum toxin can be used to treat a patient with MOUto reduce both (a) the number of headaches experienced by the patient(see FIG. 1) and (b) the daily use of acute headache pain medication bythe patient (FIG. 2). In particular, we have found (see FIG. 3) that abotulinum toxin can be used to reduce use by patients of narcotic painmedication.

Additionally, we found that patients who were overusing pain alleviationmedication experienced a significant reduction in their use of suchmedications after treatment with a botulinum toxin (see FIG. 4). We alsofound that there was a significant reduction in the intake of triptanmedications in triptan medication overuse patients (see FIG. 5).

Embodiments of the invention can also be used as part of adetoxification protocol whereby a patient who is being weaned off acutepain medications is facilitated in this goal by concurrentadministration of a botulinum toxin. Additional embodiments of theinvention can be used to treat other chronic pain conditions, including,for example, back pain, neuropathic pain, allodynia, fibromyalgia, andthe like.

In an embodiment, a method for treating an MOU patient can encompassadministration of a botulinum toxin to 31 fixed injection sites acrossseven head/neck muscles. Optionally, up to 8 additional injection sitesinto three specific muscles, where these three muscles are subset of theabove seven head/neck muscles, are administered utilizing a follow-thepain regimen to provide flexibility in the dose/muscle for the threemuscles, to address individual patient needs. In particular embodiments,a minimum of 155 units of a botulinum toxin type A up to about 195 unitsof a botulinum toxin type A, are administered in accordance with aparticular injection paradigm herein disclosed.

In a specific embodiment, a method for treating MOU comprises the stepof local administration of a botulinum neurotoxin to the frontalis,corrugator, procerus, occipitalis, temporalis, trapezius and cervicalparaspinal muscles of the MOU patient such that the botulinum neurotoxinis administered to the frontalis at about twenty units divided amongfour sites of injection, to the corrugator at about ten units dividedamong two sites of injection, to the procerus at about five units to onesite of injection, to the occipitalis at about thirty units dividedamong six sites of injection to about forty units divided among eightsites of injection; to the temporalis at about forty units divided amongeight sites of injection up to fifty units divided among ten sites ofinjection, to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, such that the total amount ofbotulinum neurotoxin administered is from about 155 units to about 195units injected at from 31 to 39 injection sites, respectively.

In an embodiment, a method for treating depression can encompassadministration of a botulinum toxin to 31 fixed injection sites acrossseven head/neck muscles. Optionally, up to 8 additional injection sitesinto three specific muscles, where these three muscles are subset of theabove seven head/neck muscles, are administered utilizing a follow-thepain regimen to provide flexibility in the dose/muscle for the threemuscles, to address individual patient needs. In particular embodiments,a minimum of 155 units of a botulinum toxin type A up to about 195 unitsof a botulinum toxin type A, are administered in accordance with aparticular injection paradigm herein disclosed.

In a specific embodiment, a method for treating ND's such as, forexample, depression, in a patient in need thereof comprises the step oflocal administration of a botulinum neurotoxin to the frontalis,corrugator, procerus, occipitalis, temporalis, trapezius and cervicalparaspinal muscles of the patient such that the botulinum neurotoxin isadministered to the frontalis at about twenty units divided among foursites of injection, to the corrugator at about ten units divided amongtwo sites of injection, to the procerus at about five units to one siteof injection, to the occipitalis at about thirty units divided among sixsites of injection to about forty units divided among eight sites ofinjection; to the temporalis at about forty units divided among eightsites of injection up to fifty units divided among ten sites ofinjection, to the trapezius at about thirty units divided among sixsites of injection up to about fifty units divided among ten sites ofinjection and to the cervical paraspinal muscles at about twenty unitsdivided among four sites of injection, such that the total amount ofbotulinum neurotoxin administered is from about 155 units to about 195units injected at from 31 to 39 injection sites, respectively.

Significantly, a method within the scope of the present invention canprovide improved patient function. “Improved patient function” can bedefined as an improvement measured by factors such as a reduced pain,reduced time spent in bed, increased ambulation, healthier attitude,more varied lifestyle and/or healing permitted by normal muscle tone.Improved patient function is may be measured with an improved quality oflife (QOL) or Health-Related Quality of Life (HRQL). QOL can beassessed, for example, using the SF-12 or SF-36 health survey scoringprocedures, or the Migraine Specific Quality of Life Questionnaire(MSQ). SF-36 assesses a patient's physical and mental health in theeight domains of physical functioning, role limitations due to physicalproblems, social functioning, bodily pain, general mental health, rolelimitations due to emotional problems, vitality and general healthperceptions. Scores obtained can be compared to published valuesavailable for various general and patient populations. TheMigraine-Specific Quality of Life Questionnaire Version 2.1 is one ofthe most frequently utilized disease-specific tools assessing the impactof migraine on HRQL. The MSQ measures the impact of migraine on thepatient's HRQL over the past 4 weeks across three dimensions: RoleFunction-Restrictive (RR), Role Function-Preventive (RP), and EmotionalFunction (EF). The MSQ was developed from an expert-based item review ofthe migraine literature and validated in a clinical sample of 458 newand stable EM patients. In the validation study the MSQ revealed highinternal consistency (Cronbach's α=0.79 to 0.85), a moderate to strongconvergent validity, as well as an adequate discriminant validity.Martin and Colleagues 21 performed a multi-center study that furthersupported the evidence of a high internal consistency (Cronbach's α=0.86to 0.96), strong reliability and good validity of the 14-item MSQ among267 participants.

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat chronic migraine withinthe scope of the present disclosure, and it is not intended to limit thescope of the invention. In the following examples various modes ofnon-systemic administration of a Clostridial neurotoxin can be carriedout. For example, by intramuscular injection, subcutaneous injection orby implantation of a controlled release implant.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred methods to treat conditions within thescope of embodiments of the present invention and are not intended tolimit the scope of the invention.

Example 1—Botulinum Toxin Type A Therapy for Headache Pain Associatedwith Chronic Migraine

In similarly designed, multicenter, randomized, placebo-controlled,phase 3 trials, 1384 adults with CM were randomized toonabotulinumtoxinA (botulinum toxin type A) (n=688) or placebo (n=696).Both studies consisted of a 28-day baseline screening period (hereafterreferred to as baseline), a 24-week, double-blind (DB) phase (2injection cycles), and a 32-week, open-label (OL) phase (3 treatmentcycles). Study visits occurred every 4 weeks and patients used a dailytelephone diary to record their headache symptoms and acute painmedications. Participants were men or women aged 18 to 65 years with ahistory of migraine meeting the diagnostic criteria listed in ICHD-II(2004) Section 1, Migraine, with the exception of “complicatedmigraine,” and with headache occurring days/month with at least 50% ofthe headache days being migraine or probable migraine days.

Botulinum toxin type A blocks the release of neurotransmittersassociated with pain genesis. As confirmed by preclinical and clinicaltrials, the presumed mechanism for headache prophylaxis is by blockingperipheral signals to the central nervous system, inhibiting centralsensitization. The fixed-site approach herein disclosed targetsdistribution of botulinum toxin type A to muscles and skin in theinnervation distribution of V1 and C2 nerves.

Based on analyses of the safety, tolerability, and efficacy of thedosing paradigms explored in previous studies, the instant injectionparadigm was developed. In this example, the particular botulinumneurotoxin utilized is onabotulinumtoxinA (BOTOX® Allergan Inc. IrvineCalif.). Injection targets included the following muscles:

Frontalis, Corrugator, and Procerus:

In the previous trials, patients most often reported thefrontal/glabellar region as the origin and end of their headache; theseand other trials showed that all 3 muscles needed injections for maximumefficacy.

Temporalis:

In previous trials, the temporalis region was the second most frequentlocation cited as the start and end of head pain. In accordance with oneaspect of the instant disclosure, a minimum dose of 20 units per sideand up to an additional 10 units (follow-the-pain strategy) total(administered to 1 or both sides in 5 unit increments) is administeredto this muscle.

Cervical Paraspinal Muscles:

In previous trials, patients indicated that their headache painfrequently started and/or stopped in the back of the head (in theoccipitalis and/or the neck). To maintain efficacy and improve overalltolerability (lower incidence of neck pain, neck rigidity, and neckmuscle weakness), in one aspect the instant injection paradigm includesthe recommendations of: (a) giving injections to the upper neck(cervical paraspinal muscles) at the base of the skull; (b) do notutilize a follow-the-pain injection regimen in the neck area; (c) keepinjections superficial and (d) reduce the total dose injected to theneck region to a fixed-site, fixed-dose of 20 units total for thismuscle group (10 units to each side of the head). Accordingly, it wasshown that this dose adjustment was successful and safe, as only 1patient here needed to use a soft collar compared to 10 in previousstudies.

Occipitalis:

In previous trials, the occipitalis was the third most frequentlyreported location for pain. In a previous study that explored thefollow-the-pain strategy, the occipitalis dose was fixed at 20 units (10units per side), whereas the highest dose allowed in this muscle inanother study was 30 units (15 units per side). The total doseadministered to the neck was reduced and thus to ensure that that therewould be sufficient “back of the head” dose to ensure efficacy, minimumdose administered to the occipitalis muscle was 30 units (15 units perside); injection sites were standardized and located primarily above theoccipital ridge to reduce the risk of neck weakness; optionalfollow-the-pain dosing with up to an additional 10 units was allowed.

Trapezius:

In previous trials, approximately 20% to 30% of patients reported thattheir headache pain started and/or ended in the trapezius muscles. Thefollow-the-pain optional injections occurred frequently for this musclegroup. Although not a general safety concern, the incidence of arm(shoulder) pain increased with higher doses; therefore, it wasdetermined that a preferred dosage regimen for the trapezius musclewould be standardized to a minimum dose of 30 units (15 units on eachside) and allow optional follow-the-pain injections to a maximum dose of50 units, if clinically needed.

Masseter:

The masseter muscle was not included as a target muscle group forinjection in the instant paradigm, as surprisingly injections to themasseter did not aid in treating migraine headaches.

In one aspect of previous trials, the highest total dose per injectioncycle evaluated was 260 units and the lowest dose was 105 units (trialone), while the second trial dose groups included 225 units, 150 units,and 75 units. In evaluating a dose response in this trial fortolerability, it was determined that the optimal total dose to maximizeefficacy and tolerability was within the range of >150 and <200 units.

In the instant example, subjects were randomized in blinded fashion(1:1) to onabotulinumtoxinA (BOTOX®) (155 units) or placebo,administered as 31 fixed-site, fixed-dose, intramuscular (IM) injectionsacross 7 specific head/neck muscle areas (frontalis, corrugator,procerus, temporalis, occipitalis, cervical paraspinal, and trapezius)(FIG. 17): Frontalis^(†) 20 units (2 sites on each side: total 4 sites);Corrugator^(†) 10 units (1 site on each side: total 2 sites) Procerus 5units (1 site); Occipitalis^(†) 30 units (3 sites on each side: total 6sites); Temporalis^(†) 40 units (4 sites on each side: total 8 sites);Trapezius^(†) 30 units (3 sites on each side: total 6 sites); Cervicalparaspinal muscles^(†) 20 units (2 sites on each side: total 4 sites).Total dose range: 155 units. Each IM injection site=0.1 mL=5 UonabotulinumtoxinA) (BOTOX®. (^(†)Dose distributed bilaterally.)

Up to an additional 40 units onabotulinumtoxinA or placebo could beadministered among 3 muscle groups (occipitalis, temporalis, ortrapezius; total of 8 sites) using a protocol-defined, follow-the-painparadigm (FIG. 17). The maximum dose was 195 units at 39 sites. The doserange per injection cycle was 155 units up to 195 units every 12 weeksfor 5 cycles.

In practicing this example, medical practitioners were instructed inaccordance with the following: dosing/administration: each 100 unit vialof onabotulinumtoxinA (BOTOX®) or placebo was diluted with 2 mLpreservative-free normal saline, resulting in a concentration of 5units/0.1 mL. Doses of 155 units to 195 units or placebo wereadministered intramuscularly using a sterile 30-gauge, 0.5-inch needle(with a Luer Lock) as injections of 0.1 mL (5 units) per site. A 1-inchneedle was allowed at the physician's discretion in the neck region forpatients with thick neck muscles. Guidelines for administeringonabotulinumtoxinA were as follows: gloves should be worn whileadministering treatment; prior to injection, the skin should be cleansedaccording to standard practice for intramuscular injection (e.g. withalcohol); the needle should be inserted into the muscle with the bevelup, at approximately a 45-degree angle; once inserted, the needle hubshould be held with 1 hand while the plunger is pulled back slightlywith the other hand to prevent torque and blood return, respectively. Ifblood returns, the needle should be reinserted into the muscle; theplunger should be pushed to administer 0.1 mL (5 units) to each site.

The following is one example of a useful order of injection foradministration of botulinum toxin in accordance with the instantdisclosure. Anatomic injection sites follow distributions and areasinnervated by the first division of the trigeminal nerve and the secondcervical nerve.

In an exemplary paradigm, a medical practitioner palpated each muscle(bilaterally, if appropriate) prior to injection to verify muscledelineation and determine the presence of muscle tenderness and/or painrequiring additional treatment. Patients were supine for injections intothe corrugator (2 injections, 1 per side), procerus (1 injection,midline), frontalis (4 injections, 2 per side), and temporalis (8injections, 4 per side), in this sequence (FIG. 17). Patients wereseated for injections into the occipitalis (6 injections, 3 per side),cervical paraspinal (4 injections, 2 per side), and trapezius (6injections, 3 per side), in this sequence (FIG. 17). If needed,additional injections into the temporalis, occipitalis, and trapeziusmuscles were allowed, using the optional follow-the-pain paradigm (FIG.17).

Post-administration, patients were observed for 10-15 minutes followingtreatment and were advised not to rub or massage the affected areas for24 hours and told that any bumps appearing on the forehead shoulddisappear within approximately 2 hours. Patients were advised that theymay need and should use their acute pain medications for breakthroughheadaches and to return at 4-week intervals and maintain a headachediary.

Pooled analyses demonstrated statistically significant differencesfavoring the herein disclosed dose of 155 to 195 units over placebo atall time points in the double blind phase across multiple headachesymptom measures, including the pooled primary endpoint of change frombaseline in frequency of headache days at 24 weeks: −8.4onabotulinumtoxinA/−6.6 placebo; p<0.001.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope ofembodiments of the present invention provided that the features includedin such a combination are not mutually inconsistent.

Example 2—Botulinum Toxin Type A Therapy for Headache Pain and for aProbable Medication Overuse Headache Disorder

A clinical study was carried out with patients who complained ofheadache pain and who took frequent acute pain medications such asnarcotics and triptans to control the pain. A botulinum toxin (BOTOX®)was administered to the patients at day 0, at day 90 and at day 180. TheBOTOX® injections were administered intramuscularly in an average of 20separate injections to each patient at each of the three injectionsessions. The BOTOX® was administered to up to seven different muscles.

From 105 to 260 units of BOTOX® was administered to each patient at eachof the three treatment sessions. It was found that the patientsexperienced a reduction in both (a) the number of headaches experiencedby such patients (FIG. 1), and; (b) the daily use of acute headache painmedication by these patients (FIG. 2). In particular, it was found (FIG.3) that a botulinum toxin can reduce use by these patients of narcoticpain medication.

Additionally, it was found that use of a botulinum toxin in patients whowere overusing pain alleviation medication resulted in a significantreduction in their use of such medications (see FIG. 4). It was alsofound that there was a significant reduction in the intake of triptanmedications in overuse patients (FIG. 5). Thus, this clinical studysurprisingly showed that a botulinum toxin can be used to treat amedication overuse headache disorder (MOU) (see FIG. 6).

The study also demonstrated (see FIG. 7) that a botulinum toxin was moreeffective in patients who were not using a concurrent headacheprophylaxis treatment regardless of any medication overuse issue.

Additionally, the same study showed (see FIGS. 8 and 9) that a botulinumtoxin was more effective in the patients who were not using a concurrentheadache prophylaxis treatment and were overusing medication. This is adiscovery in addition to our discovery that a botulinum toxin can beused to treat headache in a patient overusing acute medication, withoutregard to the fact that the patient is being treated with a botulinumtoxin monotherapy or that he or she is being treated for headache withother headache prophylaxis medications.

Furthermore, with regard to acute medication use in patients (notoveruse, but any use) the study showed that treatment of headache with abotulinum toxin resulted in a significant decrease in use of narcoticsby these patients (see e.g. day 210 in FIG. 10).

Finally, and significantly the study also showed (see FIGS. 11 and 12)that after treatment with a botulinum toxin there was a greater decreasein the frequency of headache and in the number of days acute analgesicmedications were required in the patients who were overusing triptansheadache medication at baseline, as compared to the patients who werenot overusing triptan medications. This indicates that triptans are moreeffective to treat headache when used in conjunction with a botulinumtoxin. Thus, a method for increasing the effectiveness of a triptan totreat a headache can be carried out by using a triptan and a botulinumtoxin concurrently to treat a headache.

Clinically, triptan medication overuse appears to actually cause or toexacerbate headache pain, as opposed to the alleviation of headache painwhich can result from normal triptan use. Therefore, it was a surprisingdiscovery, as set forth by FIGS. 11 and 12, to find that administrationof a botulinum toxin helps to prevent headaches in a patient populationwho have headaches, more frequent headaches or exacerbated headaches dueto triptan medication overuse. This discovery is demonstrated by studyresults and patient observations showing that triptan MOU patientsneeded less triptan medication after botulinum toxin administration.

Example 3—Botulinum Toxin Type A Therapy for Chronic Headache

This study assessed the potential benefit of BOTOX® in headacheprophylaxis in the adult chronic daily headache population. The termchronic daily or chronic near-daily headache has been used to refer tovery frequent headaches (16 or more headache days a month) not relatedto a structural or systemic illness (Silberstein and Lipton, 2001). Thekey requirement for entry into the current study was primary headachedisorder with 16 headache days per month by history and confirmed byelectronic diary during baseline. Headache disorder could include anycombination of episodic/chronic tension-type headaches, migraines withor without aura, and/or migrainous headaches (as defined by IHS criteria[Headache Classification Subcommittee of the IHS, 1988, revised 2004],and/or chronic daily headache as defined by Silberstein and Lipton,2001).

A study was conducted with a multicenter, double-blind, randomized,placebo-controlled, parallel group of multiple treatments with Botox®for the prophylactic treatment of headaches in a chronic migraineheadache population. The overall duration of the study for each patientwas 11 months. Patients were screened at Day −60 (baseline period).During this period data were collected daily from the patient regardingspecified characteristics of their headache episodes and headachemedication use for 30 days using electronic telephone diaries. Followingthe baseline period, patients returned at Day −30 (Treatment 1) for theplacebo run-in period. At this visit, patients meeting theinclusion/exclusion criteria were injected with single-masked placebo,and again recorded specified characteristics of their headache episodesfor 30 days using electronic diaries. Treatment 1 injections were in aminimum of 6 muscle areas and 23 to 58 injection sites within theseareas, dependent upon the location and severity of pain. Theinvestigator also had the option to inject the masseter if the patientwas experiencing pain in that muscle.

After 30 days (at Day 0) patients returned to be randomized forTreatment 2. Prior to randomization, using diary information collectedduring the placebo run-in period, patients were classified as a placeboresponder if they had <16 headache days or had a ≥30% decrease frombaseline in the frequency of headache days. All other patients wereconsidered placebo non-responders. Patients within each stratum(responders, non-responders) were randomized to receive either BOTOX® orplacebo at Day 0 (Treatment 2).

Patients received additional treatments at Day 90 (Treatment 3) and Day180 (Treatment 4). Patients returned for follow-up visits at 30-dayintervals following each treatment through Day 270. If a patient exitedthe study at any visit prior to Day 270 (exit), all exit procedures andevaluations were to be completed at that visit. For Treatments 2, 3, and4, patients were injected with BOTOX® or placebo using the same dose andvolume and in the same muscle areas and sites as in Treatment 1. Theschedule of study visits and measurements is shown in Table 2.

The study was randomized and double-blind to minimize investigator andpatient bias. Blinding was ensured by the similarity in appearance ofthe vials of study medication and requiring that an individual at eachstudy center who had no other study involvement reconstituted the studymedication and filled the syringes for injection. A placebo-controlled,parallel-group design eliminated possible confounding effects that areinherent in other study designs.

In contrast to the fixed site/fixed dosage treatment approach used inprevious clinical studies in the episodic migraine population,physicians participating in this study were allowed to use a moreindividualized or patient-tailored treatment approach depending on thelocation of the patient's head pain. Specifically, physicians were giventhe opportunity to determine the number of injection sites and thedosage within a protocol-specified range to be administered for thespecified frontal and posterior muscle areas of the head and neck,depending on the location and severity of a patient's headache. Maximumdose levels allowed in this study also were higher than those used inprevious studies due to the addition of injection of larger, posteriorpericranial and neck muscles.

Due to the high placebo response rate seen in previous studies, aplacebo run-in period was implemented in the present study to stratifypatients into 2 groups (placebo responders and non-responders). Duringthe placebo run-in period, patients were not informed as to whether theywere injected with BOTOX® or placebo. Furthermore, the study protocolwas amended to include 3 double-blinded treatment cycles.

Efficacy criteria were as follows. For the primary variable, adifference of 3 headache-free days between BOTOX® and placebo in themean change from baseline in the frequency of headache-free days permonth at Day 180 was considered clinically significant.

-   -   All patients enrolled in this study met at least the following        inclusion criteria: male or female, 18 to 65 years old;    -   primary headache disorder with ≥16 headache days per month by        history and confirmed by diary during baseline, which could        include any combination of migraines with or without aura,        episodic/chronic tension-type headaches, and/or migrainous        headaches (as defined by 1988 IHS criteria) (Headache        Classification Subcommittee of the IHS, 1988);    -   willing and able to give written informed consent;    -   stable medical condition;    -   stable chronic medications, if any, including non-acute,        prophylactic migraine medications, for at least 3 months        immediately prior to Day −60;    -   willing and able to stay on current medications during the        course of the study;    -   willing and able to complete the entire course of the study and        to comply with study instructions, including diary phone system.

A dose range of units to be injected into each muscle area was defined,except for the occipitalis muscle where the dosage was fixed. The numberof injection sites (total of 23 to 58 injection sites) within eachspecified muscle area (6 to 7 muscle areas) and dose injected (105 U to260 U) was determined by the physician based on the pain distributionpattern and the severity of pain in the particular muscle area. Patientswere to be injected in a minimum of 6 muscle areas, which included thefrontal/glabellar, occipitalis, temporalis, semispinalis, spleniuscapitis, and trapezius muscles, as specified in Table 1 and FIG. 13. Itwas optional to inject the masseter muscle. Patients were to be injectedwith the same dose and in the same muscle areas and sites for treatments1, 2, 3, and 4. Whenever possible, treatments for each patient were tobe performed by the same physician throughout the study.

TABLE 1 Study Medication Dose and Injection Sites Number Bilateral TotalMuscle Area of Units ^(a) Injection Dose (U) Frontal/Glabellar 25-40 No 25-40 Occipitalis 10 Yes  20 Temporalis 10-25 Yes  20-50 Masseter  0-25Yes   0-50 (optional) Trapezius 10-30 Yes  20-60 Semispinalis  5-10 Yes 10-20 Splenius capitis  5-10 Yes  10-20 Total Dose Range 105-260 Note:Patients were injected with BOTOX ® or placebo in the specified muscleswith doses determined by the investigator. ^(a) Patients randomized tothe placebo group received 0 U of BOTOX ®.

Each vial of BOTOX® contained 100 U of botulinum toxin type A, 0.5 mgalbumin (human), and 0.9 mg sodium chloride in a sterile, vacuum-driedform without a preservative. Each vial of placebo contained 0.9 mgsodium chloride in a sterile, vacuum-dried form without a preservative.The vials were stored in a freezer between −20° C. and −5° C. beforeuse. Directions for reconstitution with the diluent, 0.9% sterile saline(without preservatives), for injection were provided in the protocol.

In this study, in contrast to the fixed site/fixed dosage treatmentapproach used in previous studies, physicians were allowed to use a moreindividualized or patient-tailored treatment approach. Specifically, thenumber of injection sites (23 to 58 injection sites) within eachspecified muscle area (6 to 7 muscle areas) and dose injected (totaldose of 105 to 260 U) was determined by the physician based on thepatient's usual pain distribution pattern and the severity of pain inthe particular muscle area.

During the course of the study, the protocols were amended to include atotal of 3 treatment cycles (following the placebo run-in) and theprimary endpoint was changed to Day 180 in the placebo non-responderstratum. By the time these amendments were put in place, a significantnumber of subjects had exited the original study at the planned Day 120time point. Therefore, enrollment was extended to ensure that at least90 placebo non-responder patients (45 per treatment group) wereavailable for the Day 180 analysis.

The use of any concurrent medication (e.g., prescription orover-the-counter, including herbal remedies) was recorded on thepatient's CRF along with the reason the medication was taken. Inaddition, medications that the patient had taken for treatment of his orher headaches since 7 days prior to Day −60 were recorded on theappropriate medication CRF. During the study, the patient was to reportany use of concomitant medication for headache treatment using theelectronic telephone daily diary.

Patients taking concurrent therapies were to maintain a stable dose anddose regimen during the study, particularly with regard to the use ofnon-acute, prophylactic migraine medications. Medications that wereconsidered necessary for the patient's welfare could be given at thediscretion of the investigator. The administration of all medicationswas to be reported on the CRFs.

Efficacy Measures

Patients recorded start/stop times of headaches, maximum and averageseverity of headaches, location and type of headache pain, effect onphysical activity, presence of aura, presence of associated symptoms ofheadaches (nausea, vomiting, photo/phonophobia), and headachemedications and doses used. The primary efficacy measure was the changefrom baseline in the frequency of headache-free days in a 30 day period.The primary visit for determination of efficacy was Day 180, with theevaluation reflecting the prior 30 day period. Baseline for the efficacymeasures was defined as the frequency of headache-free days during thefirst 30 days of the screening period. A difference of 3 headache-freedays between BOTOX® and placebo in the mean change from baseline in thefrequency of headache-free days per 30-day period at Day 180 wasconsidered clinically significant.

The secondary efficacy measure was the proportion of patients with adecrease from baseline of 50% or more in the frequency of headache daysper 30-day period at Day 180. Other efficacy variables included thefollowing:

-   -   proportion of patients with a decrease from baseline of 50% or        more in the frequency of headaches per 30-day period;    -   frequency of headaches of any severity (per 30-day period);    -   frequency of migraine headaches of any severity (per 30-day        period);    -   proportion of patients with a decrease from baseline of 50% or        more in the frequency of migraine headaches per 30-day period;    -   proportion of patients with a decrease from baseline of 2 or        more migraine headaches per 30-day period;    -   moderate to severe migraine headache frequency (per 30-day        period);    -   patient's global assessment of response to treatment from        baseline, as follows:    -   −4=very marked worsening (about 100% worse or greater)    -   −3=marked worsening (about 75% worse)    -   −2=moderate worsening (about 50% worse)    -   −1=slight worsening (about 25% worse)    -   0=unchanged    -   +1=slight improvement (about 25% improvement)    -   +2=moderate improvement (about 50% improvement)    -   +3=marked improvement (about 75% improvement)    -   +4=clearance of signs and symptoms (about 100% improvement)    -   number of days per 30-day period with non-migraine headaches;    -   maximum and average headache severity (none, mild, moderate,        severe);    -   number of days that acute headache medication was used during        the study; and    -   number of uses (intakes) of acute headache mediation during the        study.

Schedule of Assessments

The frequency and timing of study visits and measurements are outlinedin Table 2 below.

TABLE 2 Schedule of Assessments Visit 2 Visit 3 (Placebo (Randomi- Visit1 Run-In/ zation/ Visit 6 Visit 9 (Baseline Treatment Treatment (Treat-(Treat- Visit 10 Visit 11 Visit 12 Period) 1) 2) Visit 4 Visit 5 ment 3)Visit 7 Visit 8 ment 4) Day Day (Exit) Day-60 Day-30 Day 0 Day 30 Day 60Day 90 Day 120 Day 150 Day 180 210 240 Day 270 View Video/Obtain

Informed Consent Inclusion/Exclusion Criteria

Review Medical and

Medication History Physical Examination

Vital Signs

Headache Diary Instructions

and Review Injection of Study

Medication Patient Global Assessment

Pain Diagram

Headache Count Recall

Beck Depression Inventory

Primary Chronic Headache

Assessment Treatment Assessment

Questionnaire MIDAS

Headache-Pain Specific

Quality of Life Questionnaire Headache Impact

Questionnaire SF-36 Health Survey

Medical Events

Adverse Events

Toxin Neutralizing

Antibody Titer Blood Draw CBC/Blood Chemistry

Urine Pregnancy Test

Menstrual Cycle Data

The primary efficacy variable was the change in the frequency ofheadache-free days from a 30 day baseline period (Day −60 to Day −31).Headache-free days in each 30 day period were determined from datarecorded in the telephone electronic diary. Data recorded in the diariesincluded headache start date and time and headache stop date and time,and the following headache characteristics: usual headache pain (mild,moderate, severe); worst headache pain (mild, moderate, severe); side ofthe head (unilateral/bilateral); type of pain (pulsating/throbbing orpressing/squeezing); and effect of physical activity on pain (worse, notworse). It also included headache symptoms: aura (yes or no);interference of activities (yes or no); and other symptoms (nausea,vomiting, sensitivity to light [photophobia], sensitivity to noise[phonophobia]). The diary data also included acute medication taken forthe headache (yes or no) and the name and dose of the medication.

Of the 571 patients screened and assessed over the Day −60 to Day −30baseline period, 355 were enrolled/randomized at Day 0. At the end ofthe run-in period (Day 0), 279 patients were classified as placebonon-responders and 76 patients as placebo responders. Subsequentlypatients were randomized within each stratum (placebo no-responders andplacebo responders) to receive either BOTOX® or placebo treatment.Within the placebo non-responder stratum, 134 patients received BOTOX®and 145 patients received placebo. Within the placebo responder stratum,39 patients received BOTOX® and 37 patients received placebo. A total of76.9% of patients (273/355) completed the study, including 132 patientswho completed the original protocol requiring only 1 post-randomizationtreatment. Of the patients who discontinued early (22.8% [81/355]): 5.1%(18/355) for lack of efficacy, 1.4% (5/355) for adverse events, 0.3%(1/355) for inability to follow study instructions, 1.1% (4/355) forpersonal reasons, and 2.8% (10/355) were lost to follow up.

There were no significant differences between treatment groups indemographic characteristics. Overall, patients were 19 to 65 years ofage (mean, 43.5 years), 84.5% (300/355) were female, and 87.9% (312/355)were Caucasian.

There were no significant differences between treatment groups inbaseline characteristics (Table 3).

TABLE 3 Baseline Characteristics (As-Treated Population) BOTOX ® 105 Uto 260 U Placebo Total Baseline Characteristic (N = 173) (N = 182) (N =355) P-value Years since onset, 14.8 (12.4) 14.2 (12.5) 14.5 (12.4)  0.655 ^(a) mean (SD) Age at onset, mean years 27.5 (12.3) 29.2 (13.6)28.4 (13.0)   0.301 ^(a) (SD) Frequency of 11.2 (6.6) 10.8 (7.9) 11.0(7.3)   0.274 migraines/probable migraines per 30 day period at baselineUse of prophylactic   56 (32.4)   71 (39.0)  127 (35.8)   0.192 ^(b)treatment, n (%) Experience menstrual   0 ( 0.0)   0 ( 0.0)   0 (0.0) >0.999 ^(b) headaches, n (%) Baseline MIDAS score, 55.3 (49.6) 59.8(59.6) 57.6 (55.0)   0.997 ^(a) mean (SD) Baseline Beck Depression 7.8 (6.9)  7.9 ( 6.8)  7.8 ( 6.9)   0.847 ^(a) Inventory score, mean (SD)Mean total dose for the 190.8 U NA NA NA second treatment cycle SD =standard deviation, NA = not applicable, MIDAS = Migraine DisabilityAssessment. ^(a) P-values for treatment comparisons from the Wilcoxonrank-sum test. ^(b) P-values for treatment comparisons from Pearson'schi-square or Fisher's exact tests.

The most common locations where head pain historically started andended, as reported by patients at baseline, are presented in Table 4.

TABLE 4 Location where Headache Pain Historically Starts and EndsReported at Baseline (Number (%) of Patients) BOTOX ® 105 U to 260 UPlacebo Total Location (N = 173) (N = 182) (N = 355) P-value HistoricalLocation Where Pain Starts Frontal/glabellar 125 (72.7) 140 (76.9) 265(74.9) 0.357 Temporalis 100 (58.1) 114 (62.6) 214 (60.5) 0.387Occipitalis  80 (46.5)  85 (46.7) 165 (46.6) 0.971 Historical LocationWhere Pain Ends Frontal/glabellar 123 (71.9) 145 (79.7) 268 (75.9) 0.089Temporalis  98 (57.3) 113 (62.1) 211 (59.8) 0.360 Occipitalis  97 (56.7)111 (61.0) 208 (58.9) 0.416

In the analyses of the frequency of headaches per 30 day period, astatistically significant change in the frequency of headaches per 30day period was observed at Days 30, 60, 150, 180, 210, and 240 forplacebo non-responders and at Day 180 for placebo responders (Table 5).FIG. 14 presents the mean baseline and the mean changes from baseline inthe frequency of headaches per 30-day period for placebo non-respondersand placebo responders.

TABLE 5 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period for PlaceboNon-responders and Placebo Responders Placebo Non-Responders PlaceboResponders Time BOTOX ® Placebo BOTOX ® Placebo Period (N = 134) (N =145) p-value ^(a) (N = 39) (N = 37) p-value ^(a) Baseline 13.1 (8.4)12.8 (9.0) 0.780 15.0 (5.0) 12.3 (4.9) 0.021 Treatment 1: Placebo(followed by a 30-day run-in period) Treatment 2 Day 30 −3.3 (5.0) −2.0(4.8) 0.028 −6.7 (6.5) −5.2 (4.7) 0.705 Day 60 −4.1 (5.5) −2.6 (5.3)0.018 −7.4 (5.7) −5.8 (4.4) 0.855 Day 90 −3.9 (5.6) −3.2 (5.9) 0.307−8.0 (6.3) −5.7 (4.5) 0.534 Treatment 3 Day 120 −4.6 (5.2) −3.0 (6.3)0.118 −7.6 (5.2) −5.6 (3.3) 0.412 Day 150 −6.3 (6.0) −3.8 (6.2) 0.039−8.5 (5.3) −6.9 (4.6) 0.851 Day 180 −6.1 (5.5) −3.1 (6.8) 0.013 −9.9(4.9) −5.6 (2.8) 0.013 Treatment 4 Day 210 −6.5 (6.9) −3.4 (7.0) 0.021−9.7 (5.8) −6.6 (4.9) 0.259 Day 240 −7.1 (7.3) −4.1 (6.5) 0.035 −9.7(6.1) −8.2 (4.5) 0.948 Day 270 −7.2 (7.4) −4.7 (7.3) 0.172 −9.9 (4.7)−7.4 (5.4) 0.488 Source: Tables 14.2-12.3 and 14.2-12.4. ^(a) Betweentreatment comparison from Wilcoxon rank-sum test.

In the analyses of other protocol-designated efficacy variables, therewere statistically significant differences between BOTOX® and placebo inthe placebo non-responder and placebo responder groups. Additionally,subgroups of patients were identified for which there was a consistentlybetter response to BOTOX® than to placebo.

Frequency of Headaches, Pooled Population

A statistically significant change in the frequency of headaches per30-day period was observed at multiple time points (Days 30, 60, 150,180, 210, and 240) (Table 6). FIG. 15 presents the mean baseline and themean changes from baseline in the frequency of headaches per 30-dayperiod. The analysis of frequency of headaches demonstratedstatistically significant differences between BOTOX® and placebo thatfavored BOTOX®.

TABLE 6 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period; Pooled PopulationBOTOX ® Placebo Time Period N = 173 N = 182 p-value ^(a) Baseline 13.5(7.7) 12.7 (8.3) 0.339 Treatment 1: Placebo (followed by a 30-day run-inperiod) Post Placebo Run-in −1.9 (4.7) −1.0 (4.0) 0.336 Treatment 2 Day30 −4.1 (5.6) −2.7 (4.9) 0.021 Day 60 −4.8 (5.7) −3.2 (5.3) 0.010 Day 90−4.9 (6.0) −3.7 (5.7) 0.135 Treatment 3 Day 120 −5.4 (5.3) −3.6 (5.8)0.061 Day 150 −6.9 (5.8) −4.6 (6.0) 0.033 Day 180 −7.1 (5.6) −3.7 (6.1)0.001 Treatment 4 Day 210 −7.4 (6.7) −4.2 (6.7) 0.005 Day 240 −7.9 (7.0)−5.1 (6.3) 0.035 Day 270 −8.0 (6.8) −5.4 (7.0) 0.080 ^(a) Betweentreatment comparison from Wilcoxon rank-sum test.

As seen in Table 6 and FIG. 15, the time of the first statisticallysignificant difference between treatment groups in the frequency ofheadaches per 30-day period was at 30 days after the first treatmentfollowing placebo run-in. At this time point, there was a significantdifference (p=0.021) between BOTOX® and placebo demonstrating a rapidonset of effect. The mean changes from baseline were −4.1 for BOTOX® and−2.7 for placebo.

TABLE 7 Number (Percentage) of Patients with a Decrease from Baseline of50% or More Headaches per 30-Day Period; Pooled Population Time PeriodBOTOX ® Placebo p-value ^(a) Treatment 1: Placebo (followed by a 30 dayrun-in period) Post Placebo Run-in 23/173 (13.3) ^(b) 20/182 (11.0)0.506 Treatment 2 Day 30 45/172 (26.2) 47/182 (25.8) 0.942 Day 60 60/164(36.6) 49/166 (29.5) 0.172 Day 90 54/149 (36.2) 49/157 (31.2) 0.352Treatment 3 Day 120 33/80 (41.3) 28/82 (34.1) 0.351 Day 150 38/75 (50.7)33/80 (41.3) 0.240 Day 180 39/72 (54.2) 30/79 (38.0) 0.046 Treatment 4Day 210 40/70 (57.1) 28/77 (36.4) 0.012 Day 240 39/70 (55.7) 32/71(45.1) 0.206 Day 270 40/69 (58.0) 38/69 (55.1) 0.731 ^(a) Betweentreatment comparison from Person's chi square test or Fisher's exacttest. ^(b) Number of patients with response/number of patients evaluatedat time period (percentage).

Table 8 presents the mean baseline and the mean changes from baseline inthe frequency of headaches per 30-day period for patients who completed2 and 3 treatment cycles after the placebo run-in period. The 138patients (69 BOTOX®, 69 placebo) who completed 3 treatment cycles had asustained response to treatment. Over the 270 day treatment period theresponse to treatment with BOTOX® generally continued to improve whilethe response to treatment with placebo remained relatively stable.

TABLE 8 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period for Patients WhoCompleted 2 or 3 Injection Cycles After the Placebo Run-in; PooledPopulation Completed 2 Treatment Cycles Completed 3 Treatment CyclesAfter Placebo After Placebo Run-in Run-in Time BOTOX ® Placebo BOTOX ®Placebo Period N = 72 N = 79 p-value ^(a) N = 69 N = 69 p-value ^(a)Baseline 14.3 (7.5) 12.8 (8.3) 0.183 14.4 (7.5) 12.6 (8.1) 0.136Treatment 1: Placebo (followed by a 30-day run-in period) Treatment 2Day 30 −4.7 (5.3) −3.4 (5.0) 0.072 −4.7 (5.4) −3.4 (5.1) 0.098 Day 60−5.3 (5.3) −3.5 (5.4) 0.037 −5.3 (5.4) −3.7 (5.6) 0.091 Day 90 −4.8(5.6) −3.5 (5.6) 0.198 −4.7 (5.7) −3.4 (5.8) 0.229 Treatment 3 Day 120−5.8 (5.2) −3.6 (5.8) 0.023 −5.7 (5.2) −3.6 (6.0) 0.036 Day 150 −6.8(5.8) −4.5 (5.9) 0.042 −6.8 (5.9) −4.5 (6.1) 0.056 Day 180 −7.1 (5.6)−3.7 (6.1) 0.001 −7.1 (5.6) −3.7 (6.3) 0.001 Treatment 4 Day 210 −7.4(6.8) −4.2 (6.7) 0.008 −7.5 (6.7) −3.9 (6.8) 0.004 Day 240 −7.9 (7.1)−5.1 (6.3) 0.030 −7.9 (7.0) −5.0 (6.3) 0.025 Day 270 −8.0 (6.8) −5.4(7.0) 0.041 −8.0 (6.8) −5.4 (7.0) 0.042 ^(a) Between treatmentcomparison from a Wilcoxon rank-sum test.

Table 9 presents the mean baseline and the mean changes from baseline inthe number of headaches with a duration ≥4 hours and <4 hours per 30-dayperiod. Over the 270-day treatment period, in headaches ≥4 hours induration, the changes from baseline headache count were significantlygreater for BOTOX® than for placebo at every return visit (p≤0.044;Table 14.5-325). A significant difference between the groups was notseen at any return visit for headaches <4 hours in duration.

TABLE 9 Mean Baseline and Change from Baseline in the Frequency ofHeadaches for Headaches of a Durations ≥4 Hours and <4 Hours per 30-DayPeriod Headaches of a Duration ≥4 Hours Headaches of a Duration <4 HoursTime BOTOX ® Placebo BOTOX ® Placebo Period N = 173 N = 182 p-value ^(a)N = 173 N = 182 p-value ^(a) Baseline 9.6 9.2 0.186 3.9 3.5 0.488Treatment 1: Placebo (followed by a 30-day run-in period) Treatment 2Day 30 −2.9 −1.2 0.001 −1.2 −1.5 0.307 Day 60 −3.4 −1.9 0.017 −1.4 −1.30.784 Day 90 −3.3 −2.0 0.024 −1.6 −1.7 0.848 Treatment 3 Day 120 −3.8−2.0 0.013 −1.6 −1.6 0.867 Day 150 −4.8 −2.8 0.044 −2.0 −1.8 0.906 Day180 −4.6 −2.2 0.005 −2.5 −1.6 0.134 Treatment 4 Day 210 −5.1 −2.4 0.003−2.3 −1.7 0.688 Day 240 −5.1 −3.0 0.016 −2.7 −2.1 0.309 Day 270 −5.5−3.1 0.013 −2.4 −2.2 0.872 ^(a) Between treatment comparison from aWilcoxon rank-sum test.

Efficacy variables for which there were clinically meaningfuldifferences between BOTOX® and placebo in this subpopulation subgroupincluded: a 50% reduction from baseline in the frequency of headachesper 30-day period; a 30% reduction from baseline in the frequency ofheadaches per 30-day period; frequency of migraines or probablemigraines per 30-day period; and, number of days and number of uses ofacute analgesic headache medication per 30-day period.

TABLE 10 Baseline Characteristics of Patients Using and Not UsingProphylactic Headache Medications at Baseline; Pooled PopulationProphylactic Headache Medications at Baseline No Yes Baseline BOTOX ®Placebo BOTOX ® Placebo Characteristic (N = 117) (N = 111) P-Value (N =56) (N = 71) P-Value Age, mean years 42.2 (10.4) 42.5 (11.5) 0.978 ^(a)44.4 (8.5) 46.5 (10.3)   0.232 ^(a) (SD) Sex, n (%) Male   11 (9.4)   22(19.8) 0.025 ^(b)   11 (19.6)   11 (15.5)   0.540 ^(b) Female  106(90.6)   89 (80.2)   45 (80.4)   60 (84.5) Race, n (%) Caucasian  102(87.2)   93 (83.8) 0.466 ^(b)   52 (92.9)   65 (91.5) >0.999 ^(b)Non-Caucasian   15 (12.8)   18 (16.2)   4 (7.1)   6 (8.5) Years sinceonset, 15.3 (13.2) 14.3 (12.8) 0.656 ^(a) 13.8 (10.7) 14.2 (12.1)  0.864 ^(a) mean (SD) Age at onset, mean 26.2 (12.2) 27.6 (13.1) 0.562^(a) 30.1 (12.1) 31.8 (13.9)   0.407 ^(a) years (SD) Prophylacticheadache medications, n (%) Beta blockers NA NA NA   16 (28.6)   21(29.6)   0.901 Calcium channel NA NA NA   9 (16.1)   18 (25.4)   0.204blockers Anticonvulsants NA NA NA   23 (41.1)   27 (38.0)   0.727Antidepressants NA NA NA   31 (55.4)   43 (60.6)   0.555 Baseline MIDAS54.0 (44.4) 55.7 (60.3) 0.302 ^(a) 58.0 (59.7) 66.1 (58.8)   0.264 ^(a)score, mean (SD) Baseline Beck  6.9 (6.6)  7.3 (7.0) 0.945 ^(a)  9.5(7.4)  8.6 (6.4)   0.739 ^(a) Depression Inventory score, mean (SD) SD =standard deviation, NA = not applicable, NC = not computed. ^(a)P-values for treatment comparisons from the Wilcoxon rank-sum test. ^(b)P-values for treatment comparisons from Pearson's chi-square or Fisher'sexact tests.

The mean baseline and mean changes from baseline to each assessment timepoint in the frequency of headache days per 30-day period are presentedin Table 11 and FIG. 16 for the populations of patients using and notusing prophylactic headache medications at baseline. The types ofprophylactic headache medications used at baseline included betablockers, calcium channel blockers, anticonvulsants, and antidepressants(excluding serotonin uptake inhibitors [e.g., PROSAC®] since there is noevidence of any effect in headache for this class).

TABLE 11 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period by Use of ProphylacticHeadache Medications at Baseline; Pooled Population Use of ProphylacticHeadache Medications at Baseline Yes No Time BOTOX ® Placebo BOTOX ®Placebo Period N = 56 N = 71 p-value ^(a) N = 117 N = 111 p-value ^(a)Baseline 12.4 (7.5) 12.5 (8.6) 0.855 14.1 (7.9) 12.9 (8.2) 0.205Treatment 1: Placebo (followed by a 30-day run-in period) Treatment 2Day 30 −2.8 (4.1) −2.8 (3.7) 0.887 −4.7 (6.1) −2.5 (5.6) 0.004 Day 60−3.5 (4.4) −3.5 (4.6) 0.836 −5.5 (6.1) −3.0 (5.7) 0.005 Day 90 −3.6(5.0) −4.8 (4.9) 0.201 −5.6 (6.3) −3.0 (6.1) 0.011 Treatment 3 Day 120−5.3 (4.3) −4.0 (4.9) 0.255 −5.5 (6.0) −3.3 (6.5) 0.072 Day 150 −5.7(5.1) −4.7 (5.3) 0.564 −7.8 (6.2) −4.5 (6.6) 0.032 Day 180 −6.6 (5.0)−3.9 (4.7) 0.030 −7.5 (6.0) −3.6 (7.3) 0.007 Treatment 4 Day 210 −6.7(5.5) −4.7 (5.1) 0.138 −7.9 (7.4) −3.7 (7.9) 0.023 Day 240 −6.6 (6.0)−5.0 (5.5) 0.279 −8.7 (7.6) −5.1 (7.1) 0.062 Day 270 −6.9 (6.3) −5.2(5.5) 0.369 −8.8 (7.1) −5.6 (8.1) 0.062 ^(a) Between treatmentcomparison from a Wilcoxon rank-sum test.

For patients using antidepressants at baseline (31 BOTOX®, 43 placebo)there were no statistically significant differences between treatmentgroups at any time point, except at Day 210 (p=0.048), in the changefrom baseline in the frequency of headaches per 30-day period. From Day120 through Day 270, the mean decrease from baseline was greater forBOTOX® by 1.6 to 3.7 headaches per 30-day period. For patients not usingantidepressants at baseline, from Day 60 through Day 270, the meandecrease from baseline was greater for BOTOX® by 1.7 to 3.6 headachesper 30-day period. The changes from baseline were significantly greater(p≤0.020) for BOTOX® at Days 30, 60, and 180.

The percentages of patients at each assessment time point with at leasta 50% decrease from baseline in the frequency of headaches per 30-dayperiod (defined as a responder) are presented in Table 12 for patientsusing and not using prophylactic headache medications at baseline.

For patients using prophylactic headache medications at baseline, therewere no statistically significant differences between BOTOX® andplacebo. For patients not using prophylactic headache medications atbaseline, from Day 150 through Day 270 at least 50% of BOTOX®-treatedpatients were responders. The differences between BOTOX® and placebowere statistically significant at Days 150 and 210. At these timepoints, the response rate for BOTOX® was greater than the response ratefor placebo by at least 20%.

TABLE 12 Number (Percentage) of Patients with a Decrease from Baselineof 50% or More Headaches per 30-Day Period by Use of ProphylacticHeadache Medications at Baseline; Pooled Population Using ProphylacticHeadache Medications at Baseline Yes No Time BOTOX ® Placebo BOTOX ®Placebo Period N = 56 N = 71 p-value ^(a) N = 117 N = 111 p-value ^(a)Treatment 1: Placebo (followed by a 30-day run-in period) Post  4/56 7/71 0.754 19/117 13/111 0.325 Placebo (7.1%) ^(b) (9.9%) (16.2%)(11.7%) Run-in Treatment 2 Day 30 10.56 17/71 0.405 35/116 30/111 0.600(17.9%) (23.9%) (30.2%) (27.0%) Day 60 15/54 20/66 0.762 45/110 29/1000.071 (27.8%) (30.3%) (40.9%) (29.0%) Day 90 15/53 22/63 0.446 39/9627/94 0.085 (28.3%) (34.9%) (40.6%) (28.7%) Treatment 3 Day 120 17/3417/39 0.584 16/46 11/43 0.345 (50.0%) (43.6%) (34.8%) (25.6%) Day 15013/30 19/38 0.584 25/45 14/42 0.037 (43.3%) (50.0%) (55.6%) (33.3%) Day180 16/28 15/38 0.155 23/44 15/41 0.146 (57.1%) (39.5%) (52.3%) (36.6%)Treatment 4 Day 210 18/29 17/38 0.159 22/41 11/39 0.021 (62.1%) (44.7%)(53.7%) (28.2%) Day 240 18/29 17/35 0.280 21/41 15/36 0.402 (62.1%)(48.6%) (51.2%) (41.7%) Day 270 16/29 19/33 0.849 24/40 19/36 0.526(55.2%) (57.6%) (60.0%) (52.8%) ^(a) Between treatment comparison fromPerson's chi-square test or Fisher's exact test. ^(b) Number of patientswith response/number of patients evaluated at time period (percentage).

The percentages of patients at each assessment time point with at leasta 30% decrease from baseline in the frequency of headaches per 30-dayperiod are presented in Table 13 for patients using and not usingprophylactic headache medications at baseline.

For patients using prophylactic headache medications at baseline, therewere no statistically significant differences between BOTOX® andplacebo. For patients not using prophylactic headache medications atbaseline, from Day 30 through Day 270 at least 50% of BOTOX®-treatedpatients had at least a 30% decrease in the frequency of headaches per30-day period. The differences between BOTOX® and placebo werestatistically significant at Days 30, 60, 150, 180, and 210. At thesetime points, the response rates for BOTOX® was greater than the responserates for placebo by 16.4 to 26.2%.

TABLE 13 Number (Percentage) of Patients with a Decrease from Baselineof 30% or More Headaches per 30-Day Period by Use of ProphylacticHeadache Medications at Baseline; Pooled Population Use of ProphylacticHeadache Medications at Baseline Time Yes No Period BOTOX ® Placebop-value ^(a) BOTOX ® Placebo p-value ^(a) Treatment 1: Placebo (followedby a 30-day run-in period) Post 15/56 18/71 0.855 24/117 29/111 0.316Placebo (26.8%) (25.4%) (20.5%) (26.1%) Run-in Treatment 2 Day 30 21/5628/71 0.824 61/116 40/111 0.012 (37.5%) (39.4%) (52.6%) (36.0%) Day 6025/54 28/66 0.671 62/110 40/100 0.018 (46.3%) (42.4%) (56.4%) (40.0%)Day 90 21/53 36/63 0.060 59/96 47/94 0.112 (39.6%) (57.1%) (61.5%)(50.0%) Treatment 3 Day 120 20/34 23/39 0.990 26/46 20/43 0.345 (58.8%)(59.0%) (56.5%) (46.5%) Day 150 18/30 26/38 0.471 35/45 24/42 0.040(60.0%) (68.4%) (77.8%) (57.1%) Day 180 20/28 24/38 0.481 33/44 20/410.013 (71.4%) (63.2%) (75.0%) (48.8%) Treatment 4 Day 210 23/29 22/380.064 28/41 18/39 0.045 (79.3%) (57.9%) (68.3%) (46.2%) Day 240 22/2923/35 0.376 31/41 22/36 0.171 (75.9%) (65.7%) (75.6%) (61.1%) Day 27020/29 23/33 0.950 30/40 23/36 0.292 (69.0%) (69.7%) (75.0%) (63.9%) ^(a)Between treatment comparison from Person's chi-square test.

Analyses of the frequency of headaches per 30-day period for patientswho were 10 to 20 years and >20 years since disease onset are given inTable 14. The response to BOTOX® was consistently better than theresponse to placebo over the entire treatment period for patients withdisease onset of 10 to 20 years with a statistically significantdifference only at Day 180 and for patients with disease onset of >20years with statistically significant differences at Days 30, 60, and210. Of note is the observation that for the >20 years subgroup ofpatients the response to placebo treatment was consistently andconsiderably lower compared with the response to treatment for the 10 to20 years subgroup of patients.

TABLE 14 Mean (Standard Deviation) Baseline and Change from Baseline inthe Frequency of Headaches per 30-Day Period by Time From Disease Onset(10 to 20 and >20 Years); Pooled Population Disease Onset 10 to 20 YearsDisease Onset >20 Years Time BOTOX ® Placebo BOTOX ® Placebo Period N =53 N = 53 p-value ^(a) N = 46 N = 48 p-value ^(a) Baseline 13.2 (7.1)11.5 (8.1) 0.170 14.1 (7.9) 14.2 (9.5) 0.931 Treatment 1: Placebo(followed by a 30-day run-in period) Treatment 2 Day 30 −3.6 (5.0) −3.4(5.1) 0.472 −4.7 (5.0) −1.9 (4.2) 0.014 Day 60 −4.9 (5.0) −4.1 (4.9)0.269 −5.8 (5.8) −1.8 (5.2) 0.003 Day 90 −4.9 (5.6) −4.4 (4.9) 0.693−5.4 (5.4) −2.8 (6.2) 0.078 Treatment 3 Day 120 −6.2 (5.8) −4.5 (5.3)0.205 −6.1 (4.7) −2.5 (6.3) 0.107 Day 150 −7.7 (6.2) −5.7 (5.1) 0.244−6.3 (5.1) −3.5 (6.6) 0.146 Day 180 −8.1 (6.4) −4.8 (5.2) 0.045 −6.1(4.6) −2.3 (6.3) 0.055 Treatment 4 Day 210 −8.3 (6.8) −6.4 (5.7) 0.256−6.7 (6.9) −1.4 (6.9) 0.025 Day 240 −8.2 (6.7) −6.1 (5.6) 0.278 −8.1(7.8) −3.4 (6.7) 0.074 Day 270 −7.4 (6.2) −6.3 (6.1) 0.481 −8.8 (8.5)−4.8 (6.9) 0.209 ^(a) Between treatment comparison from a Wilcoxonrank-sum test.

Analyses of the frequency of headaches per 30-day period by headache-dayfrequency at baseline (20 to 24 and 25 to 30 headache-days) aresummarized in Table 15. The response to BOTOX® was consistently betterthan the response to placebo over the entire treatment period forpatients with a baseline headache-day frequency of 20 to 24 withstatistically significant differences at Days 60 and 180, and forpatients with a baseline headache-day frequency of 25 to 30 withstatistically significant differences at Days 30, 60, and 180. At eachtime point, the difference between the mean changes for BOTOX® andplacebo were greater for patients with a baseline headache-day frequencyof 25 to 30.

TABLE 15 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period for Patients withHeadache-Day Frequency of 20 to 24 and 25 to 30 per 30-Day Period atBaseline; Pooled Population Headache-Day Frequency of 20 to 24Headache-Day Frequency of 25 to 30 Per 30-Day Period Per 30-Day PeriodTime BOTOX ® Placebo BOTOX ® Placebo Period N = 53 N = 54 p-value ^(a) N= 70 N = 81 p-value ^(a) Baseline 16.6 (5.9) 14.8 (6.3) 0.127 11.5(10.0) 11.5 (10.7) 0.769 Treatment 1: Placebo (followed by a 30-dayrun-in period) Treatment 2 Day 30 −5.7 (5.1) −4.2 (5.4) 0.248 −3.5 (6.4)−1.2 (4.5) 0.014 Day 60 −6.9 (5.7) −4.7 (5.6) 0.036 −3.9 (6.2) −1.4(4.9) 0.015 Day 90 −6.5 (6.1) −4.6 (5.7) 0.158 −4.0 (6.4) −2.9 (5.9)0.318 Treatment 3 Day 120 −6.9 (5.9) −4.6 (6.1) 0.166 −4.1 (5.7) −2.5(5.9) 0.154 Day 150 −9.0 (6.0) −6.4 (5.7) 0.137 −6.2 (6.5) −2.7 (5.6)0.059 Day 180 −8.9 (6.0) −5.0 (6.0) 0.038 −6.0 (6.0) −2.5 (5.8) 0.019Treatment 4 Day 210 −9.6 (7.4) −6.3 (6.1) 0.064 −6.5 (7.6) −2.4 (6.1)0.104 Day 240 −10.1 (7.2) −6.8 (5.5) 0.125 −7.5 (8.6) −3.1 (6.5) 0.057Day 270 −10.0 (6.1) −7.3 (6.1) 0.080 −7.6 (9.1) −3.3 (7.7) 0.139 ^(a)Between treatment comparison from a Wilcoxon rank-sum test.

Frequency of Headaches by Baseline Analgesic Acute Headache MedicationOveruse

Medication overuse was defined as use of any acute analgesic medicationfor 15 days and ≥2 days/week. Based on this definition, for patients whodid not have overuse of acute analgesic medications at baseline therewere no statistically significant differences between BOTOX® and placeboin the changes from baseline in the frequency of headaches per 30-dayperiod at any time point (Table 16). For patients with overuse of acuteanalgesic medications at baseline, except for Day 90, the difference inthe decrease from baseline were significantly greater for BOTOX® thanplacebo. The mean decreases from baseline were greater for BOTOX® by 2.0to 5.6 headaches at all time points, except at Day 90 (Table 16).

TABLE 16 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Headaches per 30-Day Period for Patients with AcuteAnalgesic Headache Medication Overuse (No, Yes) at Baseline; PooledPopulation Any Analgesic Overuse for 15 Days Any Analgesic Overuse for15 Days and 2 Days/Week, No and 2 Days/Week, Yes Time BOTOX ® PlaceboBOTOX ® Placebo Period N = 82 N = 105 p-value ^(a) N = 91 N = 77 p-value^(a) Baseline 11.7 (6.7) 11.1 (7.5) 0.477   15.2 (8.2) 14.9 (8.9) 0.592Treatment 1: Placebo (followed by a 30-day run-in period) Treatment 2Day 30 −3.5 (4.8) −2.8 (5.0) 0.320  −4.5 (6.1) −2.5 (4.9) 0.020 Day 60−4.0 (5.3) −3.7 (5.4) 0.756  −5.6 (5.9) −2.6 (5.2) 0.001 Day 90 −4.5(5.5) −3.7 (5.8) 0.726  −5.2 (6.4) −3.7 (5.6) 0.168 Treatment 3 Day 120−4.6 (3.9) −3.6 (6.3) 0.342  −6.2 (6.4) −3.6 (5.2) 0.044 Day 150 −5.6(4.7) −4.9 (5.7) 0.585  −8.2 (6.6) −4.3 (6.3) 0.018 Day 180 −6.1 (4.7)−3.8 (6.0) 0.088  −8.1 (6.3) −3.6 (6.4) 0.003 Treatment 4 Day 210 −5.5(5.6) −4.4 (7.1) 0.495  −9.3 (7.3) −3.9 (6.2) 0.003 Day 240 −5.7 (4.9)−5.5 (6.6) 0.885 −10.1 (8.1) −4.5 (6.1) 0.007 Day 270 −6.3 (4.9) −5.8(7.5) 0.800  −9.5 (8.0) −4.9 (6.4) 0.017 ^(a) Between treatmentcomparison from a Wilcoxon rank-sum test.

Type of Headaches

Each headache was classified as migraine (ICHD 1.) or non-migraine (ICHD2; e.g., tension-type headache). All patients experienced at least 1migraine during the baseline period, suggesting that all patients mayactually have a diagnosis of migraine even though this diagnosis was notrecognized by the investigator for all patients. During the study,patients experienced both migraine and non-migraine headaches. Themajority of headaches in both treatment groups were classified asmigraine (per the ICHD criteria).

Migraine

The mean baseline and mean changes from baseline in the frequency ofmigraine (ICHD 1.1 or 1.2) or probable migraine (ICHD 1.5.1) headachesper 30-day period are shown in Table 17. At all time points thedecreases from baseline were greater for BOTOX® compared with placeboand were significantly greater (p≤0.048) at Days 120, 180, and 210. Atthese time points the mean decreases from baseline were greater forBOTOX® by 1.6 to 2.8 headaches.

TABLE 17 Mean (Standard Deviation) at Baseline and Change from Baselinein the Frequency of Migraine and Probable Migraine Headaches per 30-DayPeriod; Pooled Population Time BOTOX ® Placebo Period N = 173 N = 182p-value ^(a) Baseline 11.2 (6.6) 10.8 (7.9) 0.274 Treatment 1: Placebo(followed by a 30-day run-in period) Treatment 2 Day 30 −3.2 (4.9) −2.7(4.4) 0.335 Day 60 −3.9 (5.2) −3.1 (5.0) 0.134 Day 90 −3.9 (5.6) −3.5(5.3) 0.768 Treatment 3 Day 120 −4.7 (5.0) −3.1 (5.5) 0.048 Day 150 −5.7(5.2) −3.7 (6.0) 0.057 Day 180 −5.8 (5.4) −3.0 (5.7) 0.002 Treatment 4Day 210 −5.9 (5.9) −3.3 (6.3) 0.018 Day 240 −6.0 (5.6) −4.2 (5.7) 0.083Day 270 −6.4 (5.8) −4.3 (6.5) 0.067 ^(a) Between treatment comparisonfrom a Wilcoxon rank-sum test.

Non-Migraine Headaches

The mean frequency of non-migraine headaches per 30-day period atbaseline was 2.3 and 1.8 in the BOTOX® and placebo groups, respectively.There were no statistically significantly differences (p≥0.065) betweenBOTOX® and placebo in the changes from baseline in the frequency ofnon-migraine headaches per 30-day period at all time points except atDay 90 (p=0.034). At all time points after the run-in period, the meandecreases from baseline were greater for BOTOX® by 0.3 to 1.0non-migraine headaches. At Day 90 the mean decrease was 1.0 for BOTOX®and 0.2 for placebo.

MOU

There were few statistically significant differences between treatmentgroups in the use of any acute headache medication (e.g. triptans,opioids, etc) during any 30-day treatment period. There were also nostatistically significant between-group differences for the individualcategories of medication, i.e., ergotamines, triptans, simpleanalgesics, or anti-emetics. There were significant differences betweentreatment groups for opioids at Day 210 (11.4% [8/70], BOTOX®, 24.7%[19/77] placebo; p=0.038 and for combination therapies at Day 210 (34.3%[24/70] BOTOX®, 18.2% [14/77] placebo; p=0.026) and Day 240 (32.9%[23/70] BOTOX®, 18.3% [13/71] placebo; p=0.048.

The baseline characteristics of patients overusing and not overusingacute analgesic headache medication at baseline at summarized in Table18. Patients overusing acute analgesic headache medications weresignificantly older at baseline (mean age, 45.6 versus 41.6 years;p=0.001), otherwise there were no statistically significant differencesbetween the demographic characteristics of overusers and non-overusersof acute analgesic headache medications at baseline.

TABLE 18 Baseline Characteristics of Patients With and Without AnalgesicHeadache Medication Overuse at Baseline; Pooled Population AnalgesicHeadache Medication Overuse ^(a) at Baseline Yes No BaselineCharacteristic N = 168 187 P-Value Age, mean years (SD) 45.6 (9.6) 41.6(11.0) 0.001 ^(b) Sex, n (%) Male   32 (19.0)   23 (12.3) 0.079 ^(c)Female  136 (81.0)  164 (87.7) Race, n (%) Caucasian  151 (89.9)  161(86.1) 0.275 ^(c) Non-Caucasian   17 (10.1)   26 (13.9) Years sinceonset, mean 15.7 (12.6) 13.5 (12.2) 0.075 ^(b) (SD) Age at onset, mean29.3 (12.4) 27.5 (13.4) 0.153 ^(b) years (SD) Prophylactic headache   61(36.3)   66 (35.3) 0.842 ^(c) medications, n (%) Beta blockers   16(9.5)   21 (11.2) 0.599 ^(c) Calcium channel   14 (8.3)   13 (7.0) 0.624^(c) blockers Anticonvulsants   23 (13.7)   27 (14.4) 0.840 ^(c)Antidepressants   38 (22.6)   36 (19.3) 0.435 ^(c) Baseline MIDAS score,54.3 (54.7) 60.6 (55.2) 0.144 ^(b) mean (SD) Baseline Beck  7.9 (6.6) 7.8 (7.1) 0.577 ^(b) Depression Inventory score, mean (SD) SD =standard deviation. ^(a) Overuse = use for ≥15 days and ≥2 days/week^(b) P-values for treatment comparisons from the Wilcoxon rank-sum test.^(c) P-values for treatment comparisons from Pearson's chi-square orFisher's exact tests.

At all post-baseline time points, in the BOTOX® compared with theplacebo group there was a greater decrease in the number of uses ofacute analgesic headache medications, with a statistically significantdifference at Days 90 and 210 (p≤0.047). This also was observed in theanalysis of the mean number of days acute analgesic headache medicationswere used, with statistically significant differences at Days 90, 180,210, and 240 (p≤0.033).

TABLE 19 Mean (Standard Deviation) at Baseline and Change from Baselinein the Number of Uses and Days of Use of Acute Analgesic HeadacheMedications per 30-Day Period for Patients Not Using ProphylacticHeadache Medications at Baseline; Pooled Population Number of Uses ofAnalgesic Acute Days with Analgesic Acute Headache Headache MedicationsMedication Use Time BOTOX ® Placebo BOTOX ® Placebo Period N = 117 N =111 p-value ^(a) N = 117 N = 111 p-value ^(a) Baseline 25.1 (17.7) 21.0(15.9)   0.058 15.5 (8.4) 13.5 (8.3) 0.069 Treatment 1: Placebo(followed by a 30-day run-in period) Treatment 2 Day 30  −8.7 (13.3)−5.7 (10.2)   0.096 −4.5 (6.3) −3.3 (5.9) 0.206 Day 60 −10.3 (14.8) −6.4(10.1)   0.076 −5.5 (7.0) −3.6 (6.6) 0.052 Day 90 −10.3 (14.2) −6.2(9.9)   0.047 −5.7 (6.7) −3.3 (6.8) 0.025 Treatment 3 Day 120 −10.0(16.7) −7.7 (9.0) >0.999 −5.7 (6.9) −4.1 (5.9) 0.427 Day 150 −13.2(16.5) −8.7 (10.6)   0.199 −7.9 (6.8) −5.2 (6.7) 0.098 Day 180 −12.9(15.5) −7.9 (11.4)   0.110 −7.8 (6.3) −4.1 (6.6) 0.015 Treatment 4 Day210 −14.6 (17.3) −7.4 (11.3)   0.018 −8.5 (7.6) −4.0 (7.4) 0.011 Day 240−15.8 (18.1) −8.5 (9.5)   0.151 −9.3 (8.1) −4.7 (7.0) 0.033 Day 270−15.6 (15.9) −9.2 (11.3)   0.093 −8.8 (7.6) −5.2 (7.3) 0.086 ^(a)Between treatment comparison from a Wilcoxon rank-sum test.

Overall, 97.7% (347/355) of patients received acute headache medicationswhile in the study, with similar proportions in each treatment group:98.3% (170/173) of patients in the BOTOX® group and 97.3% (177/182) inthe placebo group.

Overall, 87.6% (311/355) of patients received concomitant medications(other than acute headache medications), with similar proportions ineach treatment group: 90.2% (156/173) of patients in the BOTOX® groupand 85.2% (155/182) in the placebo group.

A total of 35.8% (127/355) of patients were taking a headacheprophylaxis medication during baseline. These included 10.4% (37/355) onbeta blockers, 7.6% (27/355 on calcium channel blockers, 14.1% (50/355)on anti-convulsants, and 20.8% (74/355) on anti-depressants. There wereno statistically significant differences between the BOTOX progestogensand placebo groups in the number of patients using any of theaforementioned headache prophylactic medications.

During the placebo run-in period (first treatment cycle 1, Day −30 toDay 0) all patients received placebo on Day −30. On Day 0, patients wererandomized to receive 3 treatment cycles of intramuscular injections ofBOTOX® or placebo. Of the 355 patients enrolled in the study, 173received 105 U to 260 U BOTOX® and 182 received placebo. The maximumdose of BOTOX® that patients could have received according to theprotocol was 260 U per treatment cycle for each of 3 treatment cyclesfor a total cumulative exposure of 780 U.

Dose

The mean (median) total dose of BOTOX® for the second, third, and fourthtreatment cycles was 190.8 U (200 U), 190.9 U (200 U), and 190.5 (200U), respectively. The mean and median doses of BOTOX® injected into eachmuscle group for the second, third, and fourth treatment cycles arepresented in Table 20. Of note is the observation that the optionalinjection of the masseter was administered to less than half of thepatients in both the BOTOX® and placebo groups.

TABLE 20 Mean (Median) Dose of BOTOX ® Injected into Each Muscle Groupper Treatment Muscle Injected Treatment Cycle 2 Treatment Cycle 3Treatment Cycle 4 (Allowable Dose Range) (Day 0) (Day 90) (Day 180)Frontal/glabellar (25 to 40 U) 38.0 U (40 U) 37.3 U (40 U) 37.1 U (40 U)Occipitalis (20 U) 19.8 U (20 U) 19.8 U (20 U) 19.7 U (20 U) Temporalis(20 to 50 U) 42.0 U (40 U) 42.7 U (45 U) 43.7 U (45 U) Masseter(optional; 0 to 50 U)  8.0 U (0 U)  7.6 U (0 U)  6.5 U (0 U) Trapezius(20 to 60 U) 47.4 U (60 U) 48.3 U (60 U) 48.4 U (60 U) Semispinalis (10to 20 U) 18.2 U (20 U) 18.0 U (20 U) 17.9 U (20 U) Splenius capitis (10to 20 U) 18.6 U (20 U) 18.1 U (20 U) 18.1 U (20 U) Note: Duringtreatment cycle 1 all patients were treated with placebo

The mean (median) number of sites injected with BOTOX® per muscle groupfor the first, second, and third injections are presented in Table 21.

TABLE 21 Mean (Median) Number of Sites BOTOX ® Injected per Muscle Groupper Treatment Cycle Muscle Injected Treatment Cycle 2 Treatment Cycle 3Treatment Cycle 4 (Allowable Dose Range) (Day 0) (Day 90) (Day 180)Frontal/glabellar (25 to 40 U) 9.5 (9.0) 9.8 (10.0) 9.7 (10.0)Occipitalis (20 U) 3.0 (2.0) 2.8 (2.0) 2.9 (2.0) Temporalis (20 to 50 U)6.5 (6.0) 6.3 (6.0) 6.4 (6.0) Masseter (optional; 0 to 50 U) 1.3 (0.0)1.2 (0.0) 1.2 (0.0) Trapezius (20 to 60 U) 5.9 (6.0) 6.0 (6.0) 6.0 (6.0)Semispinalis (10 to 20 U) 3.0 (2.0) 2.9 (2.0) 2.9 (2.0) Splenius capitis(10 to 20 U) 3.1 (2.0) 2.9 (2.0) 3.0 (2.0) Note: During treatment cycle1 all patients were treated with placebo.

Significant and consistent efficacy favoring BOTOX® over placebo wasobserved for the change from baseline in the frequency of headaches per30-day period. These changes were observed in the placebo non-responderand the placebo responder strata, the pooled data, and in the subgroupof patients with no baseline headache prophylactic treatment. Change inthe frequency of headache is a preferred primary endpoint in migrainetrials (European Agency for the Evaluation of Medicinal Products, 2003).Recent US FDA approved prophylactic treatment for migraine headache alsoestablished efficacy by measuring a change in frequency of headaches(Depakote package insert, 2003).

Significant differences were found between the groups favoring BOTOX® inthe percentage of patients with a decrease from baseline of at least 50%or more per 30-day period in the number of headaches at Day 180 (54.2%vs. 38.0%, p=0.046) and Day 210 (57.1% vs. 36.4%, p=0.012). In addition,the percentage of patients with a 50% decrease in headaches per 30-dayperiod occurred in more than 50% of patients at Days 150, 180, 210, 240,and 270 in the BOTOX® group, while this level was reached only at Day270 in the placebo group.

Example 4—Botulinum Toxin Type A Injection Paradigm for Treating ChronicMigraine

A clinical study was carried out to develop and optimize a dosing andinjection paradigm for administration of botulinum toxin, useful intreating migraine, particularly chronic migraine. This study developed anew method and selection of muscles to be injected; minimal, as well asoptional maximal, dose and numbers of injection sites per muscle werespecified in this study. In this study we used a preferred botulinumtoxin formulation (BOTOX®). The injection paradigm herein isparticularly useful for treating migraine patients with 15 or moreheadache days during a 28 day period. In one aspect (double blind phase)the study compared botulinum toxin administration, according to thisinjection and dosing paradigm, with placebo, as a headache prophylaxistreatment for migraine patients with 15 or more headache days per 4-weekperiod.

We discovered that injection, in a preferred embodiment, of a minimum 31to maximum 39 injection sites, minimum dose of 155 up to 195 unitmaximum administration of botulinum toxin type A (here BOTOX®) injectionparadigm detailed below, provided very positive and effective clinicaloutcomes for patients treated.

In one embodiment of a dosage paradigm utilized in Example 3,administration of 155 units to 195 units (at 31 to 39 injection sites)per treatment cycle was repeated every 12 weeks, up to a maximum of 5injection cycles. This injection paradigm, in one embodiment, required aminimum dose of 155 U using a fixed-site, fixed-dose injection regimeninto 31 sites across 7 head/neck muscles. An optional additional dose ofbotulinum toxin of up to 40 U (to up to 8 sites), using afollow-the-pain regimen, provided flexibility in the dosage per musclefor 3 muscles (temporalis, occipitalis and trapezius) to addressindividual patient needs. In utilizing the optional, additionalfollow-the-pain regimen portion of this new injection paradigm for these3 muscles (temporalis, occipitalis and trapezius), the optional andadditional botulinum toxin was administered either unilaterally orbilaterally to one or up to three of the specific head/neck muscle areas(temporalis and/or occipitalis and/or trapezius).

Turning to FIG. 17, an example of fixed locations to which doses ofbotulinum toxin was administered to patients (here administered insupine and sitting positions, for example) in accordance with one aspectof an injection paradigm, are depicted. In FIG. 17, at each siteindicated, 0.1 mL=5 U of Botulinum Toxin Type A was administered.Abbreviations utilized in FIG. 17 (under each of the muscles named),mean FSFD=Fixed site, fixed dose; FTP=optional follow-the-pain(locations and amounts of botulinum toxin administered, if utilizing theoptional follow-the-pain portion of the injection paradigm, are detailedbelow).

We have determined that the frontal/glabellar region was the mostfrequent location where head pain started and ended. We determined thatto ensure efficacy, consistency and standardization of treatment, threemuscles (frontalis, corrugators and procerus) were selected to beincluded as part of the 31 fixed site and fixed dosage muscles of theinjection paradigm of Example 2. In order to reduce the potential forfocal adverse events such as eyelid ptosis, a total dose of 35 U wasdetermined to be most advantageous. Furthermore, the exact number andlocations for injection to these muscles were specified to ensureoptimal tolerability and to specifically minimize eyelid ptosis. Indeed,the specified injection method in these muscles achieved these goalssince statistically significant separation from placebo across multipleheadache symptom measures with an overall eyelid ptosis rate for BOTOX®treated patients in the double-blind, placebo controlled phase wasfound.

In injecting these shallow muscles, the needle was preferably keptsuperficial to avoid hitting the periosteum. In one aspect, a total of 2injections was given to the corrugator muscle, one on each side of theforehead (FIG. 17, A). The injection site is located approximately 1.5cm (1 finger breadth) above the medial superior edge of the orbitalridge (bony landmark). The thumb was placed under the corrugator muscleand the injection is done with the needle angled up and away from theeye (towards the forehead), to prevent ptosis of the eyelid. In anotheraspect, the procerus muscle can have 1 injection site, which is midlineon the forehead approximately 1.5 cm above and midline to the medialsuperior aspect of the orbital ridge (bony landmark) of each eye (FIG.17, B). This injection site is substantially midway between the 2corrugator injections. In injecting the frontalis, the needle did notneed to be directed upward for these injections. A total of 4 injections(2 on the left side and 2 on the right) were given to the frontalis. Forthe 2 medial injection sites, an imaginary line up from the medial edgeof the eyebrow at about 1.5 cm (a finger breadth) from the corrugatorinjection site is a helpful method for determining needle placement(FIG. 17, C). The lateral injection sites were parallel andapproximately 1.5 cm lateral of the medial injections sites.

Turning to the temporalis, we determined that the temporalis area wasthe second most frequent location where head pain started and ended. Afixed-site, fixed-dose regimen for this muscle was utilized in thepresent injection paradigm. Because this muscle is a very commonlocation of predominant pain for many patients, a minimum dose of 20units per side (minimum 40 units total) was determined, and up to anadditional 10 units total (administered to 1 or both sides in 5 unitincrements) to this muscle group was allowed using a follow-the-painstrategy.

The temporal area received a minimum total of 8 injections, 4 to eachside (FIG. 17, D). In addition, up to 2 additional injections using theoptional follow-the-pain paradigm was used. Prior to any injection, themuscles on both sides of the head were palpated for tenderness or pain.Patient clenching of teeth assisted the physician in locating theanterior aspect of the temporalis muscle, which was then palpated. Thefirst injection was made just behind this point, trying to stay behindthe hairline. The second injection was approximately 0.5 cm superior and1.5 cm posterior to the first injection in the medial aspect of themuscle. The third injection site was parallel and approximately 1.5 cmposterior to the second injection. The fourth fixed-site injection was1.5 cm below and perpendicular to the second injection, into the medialaspect of the muscle. If additional injections (utilizing thefollow-the-pain aspect of this Example 2 injection paradigm) ofbotulinum toxin were used, additional sites of injection (rather thanincreasing the injection volume to the fixed 4 sites) were performed.

Turning to the cervical paraspinal muscle group (neck muscles), wedetermined that headache pain frequently started and/or stopped in theback of the head (either in the occipitalis and/or the neck). Thus itwas determined that for the injection paradigm utilized in this Example,injections were given to the upper neck (cervical paraspinal musclesabove the occipital ridge) at the base of the skull, rather than to themid-neck region (to avoid neck pain and neck rigidity), and thus afollow-the-pain injection regimen was not allowed in the neck region,and injections were more superficial rather than inserted deeply intothe neck muscles (in one preferred embodiment, the injection needlelength and gauge were standardized to 0.5 inch and 30 gauge,respectively) and the total dose injected to the neck region wasreduced. Thus the overall dose to the cervical paraspinal muscle groupwas a fixed-site, fixed-dose of 20 U total for this muscle group (10 Uto each side of the head divided among 4 sites (5 U per site, FIG. 17,F)). We determined that this dose is sufficient from an efficacyperspective and this particular neck dose results in less or no neckpain, less or no neck rigidity and decreased the risk of excessive neckmuscle weakness, which improved the overall tolerability profile whilemaintaining efficacy. Beginning on the left side, the cervicalparaspinal muscle group injection sites were located by palpating thecervical spine and it was preferable to not to go too deep into thecervical paraspinal and trapezius muscles with the injections (hub ofthe 0.5 inch needle serves as a relatively accurate “depth” guide). Thefirst injection was administered lateral to the midline, approximately3-5 centimeters inferior to the occipital protuberance. A secondinjection was administered on the same side, 1 cm lateral and superiorto the first injection (diagonally toward the ear from the firstinjection). This procedure was repeated symmetrically on thecontralateral side, for a total of 4 injections (fixed sites).

Relating to the trapezius, we determined that headache pain frequentlystarted and/or ended in the trapezius muscles. Thus, the dosage regimenfor the trapezius muscle was standardized to a minimum dose of 30 U (15U on each side) (to avoid/minimize arm (shoulder) pain), with the optionfor additional follow-the-pain treatment to a maximum dose of 50 U (i.e.an additional 20 units and up to 10 sites overall), if clinicallyneeded.

Accordingly, the superior portions of the trapezius muscles werepalpated to identify areas of tenderness and/or pain. Beginning on theleft side, the muscle was visually divided into 3 sections. In oneembodiment, the first injection to the trapezius was administered in thelateral aspect of the muscle. Moving medially, the mid-portion of thetrapezius was administered the second injection, while the thirdinjection was administered medially and superiorly within the thirdsection of the muscle. This procedure was repeated symmetrically on thecontralateral side for a total of 6 injections (FIG. 17, G.). Accordingto one aspect of the follow-the-pain optional dosing paradigm, anadditional 4 injections were, if needed, distributed between the rightand left trapezius muscles in the areas identified as having maximaltenderness. The infero-medial portions of the trapezius muscle wereavoided to limit the possibility of neck weakness.

Relating to the occipitalis, we determined that the occipitalis was athird most frequent location where headache pain started and ended. Inaccordance with one aspect of our new injection and dosage paradigm, theminimum dose administered to the occipitalis was 30 U at 6 sites forinjection into the occipitalis, located primarily above the occipitalridge, which reduced the risk of neck weakness. We also determined thatin order to address possible complaints of a predominant pain in theback of the head, additional follow-the-pain dosing was allowed in theoccipitalis.

Prior to injecting the occipital area, both the left and right sideswere palpated to identify the areas of tenderness and/or pain. To locatethe occipitalis injection sites, the external occipital protuberance waspalpated. The sites are superior to the supranuchal ridge on either sideof this protuberance. In one embodiment, three injections wereadministered to the right and left occipitalis muscles, for a total of 6injections (FIG. 17, E). As an example, the first injection was givenjust above the occipital protuberance along the supranuchal ridge andapproximately 1 cm left/right (depending on the side) of the externaloccipital protuberance. The second injection was given approximately 1cm to the left/right and approximately 1 cm above the first injection.The third injection was given 1 cm medial and 1 cm above the firstinjection site. According to and in one aspect of an embodiment, thefollow-the-pain optional dosing paradigm, an additional 2 injectionswere, if needed, distributed between the right and left occipitalismuscles (1 injection on each side or 2 injections on 1 side) in theareas that were identified as having maximal tenderness.

In an embodiment of our invention, the masseter muscle was not includedas a target muscle group for injection in the instant injection/dosageparadigm utilized. We surprisingly determined that even though somepatients had pain in the masseter region as part of their chronicmigraine symptoms, injection of botulinum toxin to the masseter muscleswas not necessary in order to obtain positive clinical outcomes for theheadache patients.

Thus, this paradigm, which utilizes a combination of fixed andfollow-the-pain sites for administration of botulinum toxin, providesoptimal distribution of botulinum toxin, such as a botulinum toxin typeA, based on individual patient symptoms.

Thus, in one embodiment a fixed minimum dose of 155 U and fixed numberof injection sites (31 sites) divided across 7 specific head and neckmuscles (referred to as a fixed-site, fixed-dose regimen) (Table 23)were tested. Interestingly, this protocol also allowed for a modifiedand outlined follow-the-pain regimen of up to an additional 40 U dividedacross 3 specific muscles: temporalis (up to an additional 10 U total inup to an additional 2 sites), occipitalis (up to an additional 10 Utotal in up to an additional 2 sites) and trapezius (up to an additional20 U total in up to an additional 4 sites) (Table 24). As indicatedbelow, the follow-the-pain portion regimen was not required, nor wasthere a requirement to standardize the use of follow-the-pain from oneinjection cycle to another injection cycle (toxin administered every 12weeks).

The overall study was a multicenter, double-blind, randomized,placebo-controlled, parallel-group clinical study with an open-labelextension phase, and was conducted for 60 weeks (including a 4-weekbaseline phase, followed by a 24-week, double-blind treatment phaseprior to patients entering a 32-week, open-label extension phase.Patients were randomized/stratified following a 4 week baseline phase,whereby patients meeting the inclusion/exclusion criteria were assigneda randomization number provided via a central telephone randomizationsystem. Patients were classified as medication overusers (“yes”) if theymeet 1 or more of these categories.

TABLE 22 Overuse Criteria Drug Criteria for Overuse Overall: combinedacross at least >10 days per month and at least two categories among 2days per week ergotamines, triptans, analgesics (including simpleanalgesics and combination analgesics as one category) and opioids.Ergotamine ≥10 days per month and at least 2 days per week Triptan ≥10days per month and at least 2 days per week Simple Analgesic ≥15 daysper month and at least 2 days per week Opioid ≥10 days per month and atleast 2 days per week Combination analgesic ≥10 days per month and atleast medication 2 days per week

Within each stratum, the patient was randomly allocated to receiveeither botulinum toxin or placebo in a 1:1 ratio. As to the dosage anddose regimen, two (2) treatment sessions in the double-blind phase andthree (3) treatment sessions in the open-label extension were conducted.In the double-blind phase, all patients received a minimum dose of 155 Ubotulinum toxin or placebo administered as 31 fixed-site, fixed-doseinjections across seven (7) specific head/neck muscle areas listed inTable 23. In addition, at the medical practitioner's discretion,additional injections of botulinum toxin or placebo were administeredunilaterally or bilaterally, using a follow-the-pain paradigm in up tothree (3) specific head/neck muscle areas (temporalis, occipitalis,and/or trapezius). According to one embodiment, dosing and number ofpossible injection sites are described below in table form:

TABLE 23 Required Dose Using a Fixed-Site, Fixed-Dose Injection LEFTRIGHT TOTAL Number Number Number of units of units of units per muscleper muscle permuscle (number of (number of (number of Head/Neck Areainjection sites^(a)) injection sites^(a)) injection sites^(a)) Frontalis10 (2 sites) 10 (2 sites) 20 (4 sites) Corrugator  5 (1 site)  5 (1site) 10 (2 sites) Procerus — — 5 (1 site) Occipitalis 15 (3 sites) 15(3 sites) 30 (6 sites) Temporalis 20 (4 sites) 20 (4 sites) 40 (8 sites)Trapezius 15 (3 sites) 15 (3 sites) 30 (6 sites) Cervical Paraspinal 10(2 sites) 10 (2 sites) 20 (4 sites) Muscle Group Minimum Total — — 155 U(31 sites) ^(a)1 injection site = 0.1 mL = 5 U of Botulinum Toxin Type Aor 0 U of placebo group

Optional additional injections (i.e. in addition to those detailed inTable 23) were not needed to be consistent across treatment visits, withrespect to dose or number of injection sites (as they were administeredon a case-by-case basis and at the medical practitioner's discretion,but did not exceed the maximum dose allowed (i.e. 195 units)). Wedetermined that the medical practitioner takes into accountpatient-reported usual location of predominant pain, severity of themuscle tenderness while palpating the muscle prior to injection, and themedical practitioner's best judgment on the potential benefit ofadditional doses in the specified muscles (e.g. large muscle size) indetermining how many additional units to inject above the fixed minimumamount for a particular muscle region (e.g. temporalis and/oroccipitalis and/or trapezius). Thus, in one example, the total minimumdose was 155 U with 31 head/neck injections, and the total maximum dosewas 195 U with 39 head/neck injections.

TABLE 24 Optional additional dosing using a follow-the-pain injectionparadigm: RIGHT LEFT Number of units Number of units per muscle Locationof TOTAL per muscle (number of usual pain or Number of units perHead/Neck (number of injection tenderness on muscle (number of Areainjection sites^(a)) sites^(a)) palpation injection sites^(a))Occipitalis^(b) 5 U/site 0 left side 0, 5 or 10 U (up to 2 sites) (0, 1or 2 sites) 0 5 U/site right side (up to 2 sites) 5 U (1 site) 5 U (1site) both sides Temporalis^(b) 5 U/site 0 left side 0, 5 or 10 U (up to2 sites) (0, 1 or 2 sites) 0 5 U/site right side (up to 2 sites) 5 U (1site) 5 U (1 site) both sides Trapezius^(b) 5 U/site 0 left side 0, 5,10, 15 or 20 U (up to 4 sites) (0, 1, 2, 3 or 4 sites) 5 U/site 5 U (1site) (up to 3 sites) 0 5 U/site right side (upt o 4 sites) 5 U (1 site)5 U/site (up to 3 sites) 5 U/site 5 U/site both sides (up to 2 sites)(up to 2 sites) Max. 40 U (8 sites) additional Max. Total 195 U (39sites) ^(a)1 injection site = 0.1 mL = 5 U of Botulinum Toxin Type A or0 U of placebo group ^(b)Maximum additional dose distributedunilaterally or bilaterally is as follows: Occipitalis = 10 U,Temporalis = 10 U, Trapezius = 20 U

During the baseline phase of this example (Week −4 to Day 0) the patienthad at least 15 headache days and at least 4 headache episodes of anytype each with a minimum duration of 4 hours. At least 50% of theseheadache episodes were classified as migraine (ICHD-II 1.1 or 1.2), orprobable migraine (ICHD-II 1.6). After the 4-week baseline phase,prospective patients returned to the investigators office to qualify forentry into the 24-week double-blind treatment phase. Women ofchildbearing potential had a negative urine pregnancy test prior toentry into the 4-week baseline phase and also prior to the firstinjection of study medication at Day 0.

Accordingly and as one example, a combined fixed site and follow-thepain paradigm of botulinum toxin dosing and administration sites, havinga minimum number of head, neck, shoulder areas to be administered aminimum amount of botulinum toxin, along with a subset of those head,neck, shoulder areas to which additional botulinum toxin can beadministered (up to a stated maximum dosage, such as a maximum dosageenumerated in a package insert or prescribing information is disclosed.

1. A method for treating or reducing the occurrence of a headache in apatient with a medication overuse headache disorder, the methodcomprising: local administration of a botulinum neurotoxin to 31 fixedinjection sites across seven head and neck muscles, and optionally up to8 additional injection sites into three specific muscles, wherein thesethree muscles are subset of the seven head and neck muscles, to therebytreat or reduce the occurrence of headache in the patient.
 2. The methodof claim 1, wherein the 31 fixed injection sites across the seven headand neck muscles comprise four injection sites in the frontalis; twoinjection sites in the corrugator; one injection site in the procerus;six injection sites in the occipitalis; eight injection sites in thetemporalis; six injection sites in the trapezius and four injectionsites in the paraspinal muscles.
 3. The method of claim 1, wherein the 8additional injection sites into three specific muscles comprise twoinjection sites in the occipitalis; two injection sites in thetemporalis; and four injection sites in the trapezius.
 4. The method ofclaim 1, wherein the botulinum neurotoxin is serotype A.
 5. The methodof claim 1, wherein the administration is by injection.
 6. The method ofclaim 1, wherein the administration is by subcutaneous injection.
 7. Themethod of claim 1, wherein the administration is by intramuscularinjection.
 8. A method for treating or reducing the occurrence of aheadache in a patient with episodic migraine, the method comprising:local administration of a botulinum neurotoxin to 31 fixed injectionsites across seven head and neck muscles, and optionally up to 8additional injection sites into three specific muscles, wherein thesethree muscles are subset of the seven head and neck muscles, to therebytreat or reduce the occurrence of headache in the patient.
 9. The methodof claim 8, wherein the 31 fixed injection sites across the seven headand neck muscles comprise four injection sites in the frontalis; twoinjection sites in the corrugator; one injection site in the procerus;six injection sites in the occipitalis; eight injection sites in thetemporalis; six injection sites in the trapezius and four injectionsites in the paraspinal muscles.
 10. The method of claim 8, wherein the8 additional injection sites into three specific muscles comprise twoinjection sites in the occipitalis; two injection sites in thetemporalis; and four injection sites in the trapezius.
 11. The method ofclaim 8, wherein the botulinum neurotoxin is serotype A.
 12. The methodof claim 8, wherein the administration is by injection.
 13. The methodof claim 8, wherein the administration is by subcutaneous injection. 14.The method of claim 8, wherein the administration is by intramuscularinjection.
 15. The method of claim 8, wherein the botulinum neurotoxinis onabotulinumtoxinA.
 16. The method of claim 11, wherein the totalamount of botulinum toxin type A administered is from about 155 units toabout 195 units of onabotulinumtoxinA.
 17. The method of claim 11,wherein the total amount of botulinum toxin type A administered to the31 injection sites is about 155 units of onabotulinumtoxinA.
 18. Themethod of claim 8, wherein the botulinum toxin is a pure botulinumtoxin.
 19. The method of claim 18, wherein the pure botulinum toxin isincobotulinumtoxinA.
 20. The method of claim 11, wherein the totalamount of botulinum toxin type A administered is from about 155 units toabout 195 units of incobotulinumtoxinA.
 21. The method of claim 11,wherein the botulinum neurotoxin type A is abobotulinumtoxinA.
 22. Themethod of claim 11, wherein the total amount of botulinum toxin type Aadministered is from about 310 units to about 975 units ofabobotulinumtoxinA.
 23. The method of claim 11, wherein the total amountof botulinum toxin type A administered to the 31 injection sites isabout 310 units of abobotulinumtoxinA.
 24. The method of claim 8,wherein the botulinum neurotoxin is serotype B.
 25. The method of claim8, wherein the botulinum neurotoxin is type E.